Carboxamide-pyrimidine derivatives as SHP2 antagonists

ABSTRACT

The invention relates to carboxamide-pyrimidine derivatives of the general formula I, 
                         
or a pharmaceutically acceptable salt thereof, and the use of the compounds of the present invention for the treatment of hyperproliferative diseases and disorders in mammals, especially humans, and pharmaceutical compositions containing such compound.

This application is a divisional of U.S. patent application Ser. No.16/813,192, filed on Mar. 9, 2020, which claims the benefit of EPapplication number 19161323.1, filed on Mar. 7, 2019 and U.S.Provisional Application No. 62/879,597 filed Jul. 29, 2019, the contentsof which are incorporated in their entirety by reference.

The invention relates to carboxamide-pyrimidine derivatives of thegeneral Formula I,

and the use of the compounds of the present invention for the treatmentand/or prevention of hyperproliferative diseases and disorders inmammals, especially humans, and pharmaceutical compositions containingsuch compounds.

BACKGROUND OF THE INVENTION

Src homology region 2 (SH2) containing protein tyrosine phosphatase 2(SHP2) is a non-receptor protein tyrosine phosphatase encoded by thePTPN11 gene that contributes to multiple cellular functions includingproliferation, differentiation, cell cycle maintenance and migration.SHP2 is involved in signaling through the Ras-mitogen-activated proteinkinase, the JAK-STAT or the phosphoinositol 3-kinase-AKT pathways. SHP2has two N-terminal Src homology 2 domains (N—SH2 and C—SH2), a catalyticdomain (PTP), and a C-terminal tail. The two SH2 domains control thesubcellular localization and functional regulation of SHP2. The moleculeexists in an inactive, self-inhibited conformation stabilized by abinding network involving residues from both the N—SH2 and PTP domains.Stimulation by, for example, cytokines or growth factors leads toexposure of the catalytic site resulting in enzymatic activation ofSHP2.

SHP2 is ubiquitously expressed in various tissues and cell types. Itplays an important role in diverse signaling pathways to regulatecellular biological processes and is involved in the signaling pathwaysof a variety of growth factors and cytokines. Within a single signalingpathway, SHP2 can play both positive (signal enhancing) and negative(signal diminishing) roles intracellular signaling processes. SHP2 isbelieved to function by dephosphorylating its associated signalingmolecules, thereby attenuating the local signaling flow. However, themain effect of SHP2 action in most signaling pathways (e.g. growthfactor, cytokine and extracellular matrix receptors) is to enhancesignal transduction. For example, SHP2 is a positive regulator of theERK/MAPK signaling pathway, playing a key role in regulating cellularproliferation and survival (K. S. Grossman et al., Adv. Cancer Res.,2010, 106, 53-89 and references cited therein).

Mutations in the PTPN11 gene that affect the N—SH2 or PTP domainresidues involved in basal inhibition of SHP2 result in more readilyactivatable forms of SHP2 protein, which can lead to unregulated orincreased SHP2 activity. Such activated mutants of SHP2 have beenassociated with developmental disorders such as Noonan syndrome, wherenearly all mutated forms of SHP2 demonstrate increased PTP activity.Activating SHP2 mutations have also been detected in juvenilemyelomonocytic leukemia (e g. Q506P), chronic myelomonocytic leukemia(e.g. Y63C), neuroblastoma (e.g. T507K), melanoma (e.g R138Q), acutemyeloid leukemia (e.g, G503V), breast cancer, lung cancer (e.g. E76V)and colorectal cancer (e.g. E76G) (M. Bentires-Alj er al., in CancerRes. 2004, 64, 8816-8820; and references cited therein). AdditionalPTPN1 mutations associated with cancers are disclosed in WO 2015/107495and references cited therein.

Mutations in the PTPN11 gene and subsequently in SHP2 have beenidentified in several human diseases, such as Noonan Syndrome (NS),Leopard Syndrome, diabetes, neutropenia (Kostmann's syndrome), systemiclupus erythematosus, neuroblastoma, melanoma, juvenile myelomonocyticleukemia, acute myeloid leukemia, juvenile leukemia, chronicmyelomonocytic leukemia and other cancers associated with SHP2deregulation such as cancers of the lung, colon and breast such asHER2-positive breast cancer, triple-negative breast cancer, ductalcarcinoma of the breast, invasive ductal carcinoma of the breast,non-small cell lung cancer (including adenocarcinoma of the lung),esophageal cancer, gastric cancer, squamous-cell carcinoma of hhe headand neck (SCCHN) and colon cancer. (N. Aceto et al., Nature Medicine,2012, 28, 529-538; C. M. Furcht et al., Oncogene, 2013, 32, 2346-2355;V. E. Schneeberger et al., Oncotarget, 2015, 6, 6191-6202; P. Cai etal., Biomedicine & Pharmacotherapy 2014, 6, 285-290; and referencescited therein).

Therefore, SHP2 represents a highly attractive target for thedevelopment of novel therapies for the treatment of various diseases.The compounds of the present disclosure fulfill the need for smallmolecules to that inhibit the activity of SHP2.

SHP2 phosphatase inhibitors are disclosed e.g. in WO 2015/107493. WO2015/107494, WO 2015/107495, WO 2016/203404, WO 2016/203405, WO2016/203406, WO2017/216706, WO2018/013597, WO2018/136264, WO2018/136265,WO2018/057884, WO2018/081091 and J. G. Fortanet et al., J. Med. Chem.2016, doi: 10.1021/acs.jmedchem.6b00600 and references cited therein.The effects of SHP2 phosphatase inhibition are described e.g. in Y.-N.P. Chen et al., Nature, 2016, doi. 10.1038/nature/18621; J. Wang et al.,J. Clin. Invest., 2016, 126, 2077-2092 and references cited therein.SHP2 phosphatase inhibitors include e.g.8-Hydroxy-7-[(6-sulfo-2-naphthyl)azo]-5-quinolinesulfonic acid (NSC87077) and SHP099.

However, known compounds such as SHP099 (or the compounds of theWO2015/107493) and/or RMC-4550 (the compounds of the WO2018/013597) donot show a high selectivity over hErg which is very important for thesafety of compounds which are intended to be used for the prevention ortreatment of diseases.

Furthermore, the compounds of the present invention show superiorpharmacokinetic properties (e.g., low clearance and/or high exposure) ascompared to known compounds such as SHP099 (or the compounds of theWO2015/107493) or RMC-4550 (the compounds of WO2018/013597).

Thus, there remains a need for highly effective SHP2 inhibitors which donot show the described disadvantages. It was a specific object of theinvention to provide improved methods of preventing or treatinghyperproliferative diseases and disorders in a host, especially toprovide effective SHP2 antagonists for the treatment and prevention ofsuch diseases.

SUMMARY OF THE INVENTION

Surprisingly, it has been found that the carboxamide-pyrimidinederivatives according to the invention are highly effective inhibitorsof SHP2 and thus they can be used for the treatment ofhyperproliferative diseases and disorders such as cancer.

Additionally, the compounds of the present invention are highlyeffective inhibitors of ERK1 2, a target downstream form SHP2 in thesignaling pathway (as mentioned above SHP2 is a positive regulator ofthe ERK/MAPK signaling pathway, ERK phosphorylation depends on SHP2activation), which is playing a key role in regulating cellularproliferation and survival. This also confirms that the compounds of thepresent invention can be used for the treatment of hyperproliferativediseases and disorders such as cancer.

At the same time, the compounds of the present invention in comparisonwith the known SHP2 antagonists SHP099, RMC-4550 and similar pyrimidinederivatives surprisingly have a much higher selectivity over hErg (theion channel Kv11.1). The high hErg inhibitory activity of SHP099,RMC-4550 and similar pyrimidine derivatives clearly point to a potentialcardiotoxicity risk, which is avoided by the compounds of the presentinvention. This improved safety profile of the compounds of the presentinvention is combined with the more desirable pharmacokinetic propertiesand enhanced target engagement (lower IC50s). The surprising propertiesof the compounds of the present invention show a significant neededadvancement in the field of SHP2 inhibitors.

The invention relates to carboxamide-pyrimidine derivatives of thegeneral Formula I*,

-   -   wherein    -   R1 is mono- or bicyclic alkyl, heterocyclyl, heteroaryl or        bicyclic alkylaryl, containing 3 to 14 carbon atoms and 0-4        heteroatoms, independently selected from N, O and S, which is        unsubstituted or mono-, di- or trisubstituted by (CH₂)_(n)NH₂,        (CH₂)_(n)OH, (CH₂)_(n)CH₃ or Hal,    -   X is a single bond, —NH— or —N(CH₃)—, (CH₂), or O,    -   R2 is aryl or heteroaryl, S-aryl or S-heteroaryl which is        unsubstituted or mono-, di- or trisubstituted by (CH₂)_(n)NH₂,        (CH₂)_(n)OH, COOH, CONH₂, alkyl, ═S, ═O, ═NH, CN or Hal,    -   R3 is H, NH₂, OH, Hal or alkyl,    -   Y is N or O,    -   R4, R5 are both H or one of R4 and R5 is OH, COOH, NH₂, CONH₂ or        methyl or ethyl which is unsubstituted or substituted by ═S, ═O,        OH, COOH, ═NH, NH₂, CONH₂,    -   Hal is F, Cl, Br, or I,    -   n is 0, 1, 2 or 3,

and physiologically acceptable salts, derivatives, solvates, prodrugs,stereoisomers and atropisomers thereof, including mixtures thereof inall ratios.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 depicts the mixture of compounds (117+118) suppressed MCP-1production in U937 cells stimulated with IL-6.

DETAILED DESCRIPTION OF THE INVENTION

The invention preferably relates to carboxamide-pyrimidine derivativesof the general formula I,

or a pharmaceutically acceptable salt thereof, wherein

R1 is a monocycloalkyl, bicycloalkyl, monoheterocyclyl or biheterocyclylany of which is optionally spiro connected to a monocycloalkyl,bicycloalkyl, monoheterocyclyl, or biheterocyclyl, each of which mono-or bi-cycloalkyl and heterocyclyl may be each optionally andindependently substituted with 1-3 groups selected from C₁-C₆ alkyl, —F,—Cl, —CF₃, —NH₂, C₁-C₃ aminoalkyl, —OH, C₁-C₃ alkoxy, C₁-C₃ hydroxyalkyland phenyl;

X is a bond, —NH— or —N(Me)-;

R2 is an aryl or heteroaryl which is substituted with 1-3 groupsselected from —F, —Cl, —CF₃, C₁-C₃ alkoxy and C₁-C₃ alkyl;

R3 is —H, —NH₂, —OH, —Cl, —F, —Br, or —CH₃;

Y is —N—; and

R4 and R5 are independently —H, —NH₂, —OH, C₁-C₃ alkyl, or C₁-C₃hydroxyalkyl. The invention preferably relates to carboxamide-pyrimidinederivatives of the general Formula Ia,

or a pharmaceutically acceptable salt thereof, wherein each of R6, R7and R8 are independently selected from —H, —F, —Cl, —CF₃, C₁-C₃ alkoxyand C₁-C₃ alkyl, and the rest of the variables are as described forcompounds of Formula I.

The invention preferably relates to carboxamide-pyrimidine derivativesof the general formula Ib,

or a pharmaceutically acceptable salt thereof, wherein

R1 is

when A is the point of attachment to the pyrimidine ring of Formula Ib;

each of R6, R7 and R8 are independently selected from —H, —F, —Cl, —CF₃,C₁-C₃ alkoxy and C₁-C₃ alkyl;

n is 0, 1, 2, or 3; and

each of R9, R10, R11, R12, R13, R14, R15 and R16, when present, areindependently selected from —H, C₁-C₃ alkyl, —NH₂, —OH, —Cl, —F, —Br,C₁-C₃ aminoalkyl, C₁-C₃ hydroxyalkyl, C₁-C₃ alkoxy, and phenyl; or

two of R9, R11, R13 and R16 are taken together to form a bridgedbicyclic heterocyclic system which is optionally substituted with 1-3substituents selected from C₁-C₃ alkyl, —NH₂, —OH, —Cl, —F, —Br, C₁-C₃aminoalkyl, C₁-C₃ hydroxyalkyl, C₁-C₃ alkoxy, and phenyl; or

two of R9, R10, R11, R12, R13, R14, R15, and R16, which are attached tothe same carbon atom, are taken together to form a monocyclic orbicyclic spirocyclyl, which is optionally substituted with 1-3substituents selected from C₁-C₃ alkyl, —NH₂, —OH, —Cl, —F, —Br, C₁-C₃aminoalkyl, C₁-C₃ hydroxyalkyl, C₁-C₃ alkoxy, and phenyl; or

two of R9, R10, R11, R12, R13, R14, R15, and R16, which are attached toadjacent carbon atoms, are taken together to form a fused carbocyclyl orheterocyclyl, which is optionally substituted with 1-3 substituentsselected from C₁-C₃ alkyl, —NH₂, —OH, —Cl, —F, —Br, C₁-C₃ aminoalkyl,C₁-C₃ hydroxyalkyl, C₁-C₃ alkoxy, and phenyl;

and the rest of the variables have the meanings as described for FormulaI above.

The invention preferably relates to carboxamide-pyrimidine derivativesof the general Formula Ic,

and wherein the rest of the variables have the meanings as described forFormula I above.

The invention preferably relates to carboxamide-pyrimidine derivativesof the general Formula Id,

wherein the rest of the variables have the meanings as described forFormula I above.

The invention preferably relates to carboxamide-pyrimidine derivativesof the general Formula Ie,

wherein the rest of the variables have the meanings as described forFormula I above.

The invention preferably relates to carboxamide-pyrimidine derivativesof the general Formula If,

wherein the rest of the variables have the meanings as described forFormula I above.

The invention preferably relates to a compound according to Formula I orFormula Ia, wherein R1 is one of the following structures:

which is unsubstituted or mono-, di- or trisubstituted by C₁-C₆ alkyl,—F, —Cl, —CF₃, —NH₂, C₁-C₃ aminoalkyl, —OH, C₁-C₃ alkoxy, or C₁-C₃hydroxyalkyl,

and wherein X, R2, R3, Y, R4 and R5 have the meanings as disclosedabove.

The invention more preferably relates to a compound according to FormulaI or Formula Ia, wherein X—R1 is one of the following structures:

wherein A represents the point of attachment to the pyrimidine ring, andwherein the rest of the variables have the meanings as described for theformulae.

In one aspect of the present invention, for Formula I or Formula Ia,X—R1 is selected from the group consisting of:

wherein A represents the point of attachment to the pyrimidine ring.

In one aspect of the present invention, for Formula I or Formula Ia,X—R1 is selected from the group consisting of:

wherein A represents the point of attachment to the pyrimidine ring.

In one aspect of the present invention, for Formula I or Formula Ia,X—R1 is selected from the group consisting of:

wherein A represents the point of attachment to the pyrimidine ring.

The invention preferably relates to a compound according to Formula I,or a pharmaceutically acceptable salt thereof, wherein R2 is phenylwhich is unsubstituted or mono-, di- or trisubstituted by —F, —Cl and/or—Br, and wherein X, R1, R3, Y, R4 and R5 have the meanings as disclosedabove.

The invention preferably relates to a compound according to Formula I,or a pharmaceutically acceptable salt thereof, wherein R2 is one of thefollowing structures:

and wherein X, R1, R3, Y, R4 and R5 have the meanings as disclosedabove.

The invention preferably relates to a compound according to Formula I,or a pharmaceutically acceptable salt thereof, wherein R3 is —NH₂, andwherein X, R1, R2, Y, R4 and R5 have the meanings as disclosed above.

The invention preferably relates to a compound according to Formula I,or a pharmaceutically acceptable salt thereof, wherein R3 is —CH₃, andwherein X, R1, R2, Y, R4 and R5 have the meanings as disclosed above.

The invention preferably relates to a compound according to Formula I,or a pharmaceutically acceptable salt thereof, wherein R3 is —H, andwherein X, R1, R2, Y, R4 and R5 have the meanings as disclosed above.

The invention preferably relates to a compound according to Formula I,or a pharmaceutically acceptable salt thereof, wherein R3 is —Cl, andwherein X, R1, R2, Y, R4 and R5 have the meanings as disclosed above.

The invention preferably relates to a compound according to Formula I,or a pharmaceutically acceptable salt thereof, wherein X is a singlebond, —NH— or —N(CH₃)—, and wherein Y, R1, R2; R3, R4 and R5 have themeanings as disclosed above.

In one aspect of the present invention is a compound according toFormula Ib, or a pharmaceutically acceptable salt thereof, wherein R1 is

when A is the point of attachment to the pyrimidine ring of Formula Ib;

each of R6, R7 and R8 are independently selected from —H, —F, —Cl, —CF₃,C₁-C₃ alkoxy and C₁-C₃ alkyl;

n is 0, 1, 2, or 3; and

each of R9, R10, R11, R12, R13, R14, R15 and R16, when present, areindependently selected from —H, C₁-C₃ alkyl, —NH₂, —OH, —Cl, —F, —Br,C₁-C₃ aminoalkyl, C₁-C₃ hydroxyalkyl, C₁-C₃ alkoxy, and phenyl; or

two of R9, R11, R13 and R16 are taken together to form a bridgedbicyclic heterocyclic system which is optionally substituted with 1-3substituents selected from C₁-C₃ alkyl, —NH₂, —OH, —Cl, —F, —Br, C₁-C₃aminoalkyl, C₁-C₃ hydroxyalkyl, C₁-C₃ alkoxy, and phenyl; or

two of R9, R10, R11, R12, R13, R14, R15, and R16, which are attached tothe same carbon atom, are taken together to form a monocyclic orbicyclic spirocyclyl, which is optionally substituted with 1-3substituents selected from C₁-C₃ alkyl, —NH₂, —OH, —Cl, —F, —Br, C₁-C₃aminoalkyl, C₁-C₃ hydroxyalkyl, C₁-C₃ alkoxy, and phenyl; or

two of R9, R10, R11, R12, R13, R14, R15, and R16, which are attached toadjacent carbon atoms, are taken together to form a fused carbocyclyl orheterocyclyl, which is optionally substituted with 1-3 substituentsselected from C₁-C₃ alkyl, —NH₂, —OH, —Cl, —F, —Br, C₁-C₃ aminoalkyl,C₁-C₃ hydroxyalkyl, C₁-C₃ alkoxy, and phenyl.

The invention particularly preferably relates to a compound selectedfrom the group consisting of:

No. IUPAC-Name 1

2-(4-amino-4-methylpiperidin-1-yl)- 5-(2,3-dichloro-phenyl)-pyrimidine-4-carboxamide 2

6-Amino-2-(4-amino-4-methyl- piperidin-1-yl)-5-(3-chloro-phenyl)-pyrimidine-4-carboxylic acid amide 3

6-Amino-2-(4-amino-4-methyl- piperidin-1-yl)-5-(2,3-dichloro-phenyl)-pyrimidine-4-carboxylic acid amide 4

6-Amino-2-(4-amino-4-methyl- piperidin-1-yl)-5-(3-fluoro-phenyl)-pyrimidine-4-carboxylic acid amide 5

6-amino-2-[(3S,4S)-4-amino-3- methyl-2-oxa-8-azaspiro-[4.5]decan-8-yl]-5-(2,3- dichlorophenyl)pyrimidine-4- carboxamide 6

6-amino-2-{9-amino-3- azabicyclo[3.3.1]nonan-3-yl}-5-(2,3-dichlorophenyl)pyrimidine-4- carboxamide 7

6-amino-2-[(1R)-1-amino-8- azaspiro[4.5]decan-8-yl]-5-(2,3-dichlorophenyl)pyrimidine-4- carboxamide 8

6-amino-2-[(1R)-1-amino-3,3- difluoro-8-azaspiro[4.5]decan-8-yl]-5-(2,3-dichlorophenyl)pyrimidine-4- carboxamide 9

6-Amino-2-(4-amino-4-methyl- piperidin-1-yl)-5-(2,3-dichloro-phenyl)-pyrimidine-4-carboxylic acid methylamide 10

6-amino-2-[6-amino-7-hydroxy-1- (propan-2-yl)-2-azaspiro[3.4]octan-2-yl]-5-(2,3- dichlorophenyl)pyrimidine-4- carboxamide 11

6-amino-2-[8-(aminomethyl)-6- azaspiro[3.4]octan-6-yl]-5-(2,3-dichlorophenyl)pyrimidine-4- carboxamide 12

6-amino-2-[3-(aminomethyl)-8- azabicyclo[3.2.1]octan-8-yl]-5-(2,3-dichlorophenyl)pyrimidine-4- carboxamide 13

6-amino-5-(2,3-dichlorophenyl)-2- [(1R,7S,11s)-11-amino-1,7- dimethyl-9-azabicyclo[5.3.1]undecan-9- yl]pyrimidine-4-carboxamide 14

6-amino-5-(2,3-dichlorophenyl)-2- [(1R,7S,11r)-11-amino-1,7- dimethyl-9-azabicyclo[5.3.1]undecan-9- yl]pyrimidine-4-carboxamide 15

2-(4-Amino-4-methyl-piperidin-1-yl)- 5-(2,3-dichloro-phenyl)-6-hydroxy-pyrimidine-4-carboxylic acid amide 16

2-(4-Amino-4-methyl-piperidin-1-yl)- 6-chloro-5-(2,3-dichloro-phenyl)-pyrimidine-4-carboxylic acid amide 17

6-Amino-2-(4-amino-4-methyl- piperidin-1-yl)-5-(2,3-dichloro-phenyl)-pyrimidine-4-carboxylic acid (2-hydroxy-ethyl)-amide 18

2-(4-Amino-4-methyl-piperidin-1-yl)- 5-(2,3-dichlorophenyl)-6-methyl-pyrimidine-4-carboxylic acid amide 19

2-(4-Amino-4-methyl-piperidin-1-yl)- 6-chloro-5-(3-fluoro-phenyl)-pyrimidine-4-carboxylic acid amide 20

6-Amino-2-(4-amino-4-methyl- piperidin-1-yl)-5-(2,3-dichloro-phenyl)-pyrimidine-4-carboxylic acid hydroxyamide 21

6-Amino-2-(4-amino-4-methyl- piperidin-1-yl)-5-(2,3-dichloro-phenyl)-pyrimidine-4-carboxylic acid hydrazide 22

2-(4-Amino-4-methyl-piperidin-1-yl)- 6-fluoro-5-(3-fluoro-phenyl)-pyrimidine-4-carboxylic acid amide 23

6-amino-2-[4-(aminomethyl)-8-oxa- 2-azaspiro[4.5]decan-2-yl]-5-(2,3-dichlorophenyl)pyrimidine-4- carboxamide 24

2-[3a-(aminomethyl)-octahydro-1H- isoindol-2-yl]-6-amino-5-(2,3-dichlorophenyl)pyrimidine-4- carboxamide 25

2-(4-Amino-4-methyl-piperidin-1-yl)- 5-(3-fluoro-phenyl)-6-hydroxy-pyrimidine-4-carboxylic acid amide 26

(4M)-6-amino-2-(4-amino-4- methylpiperidin-1-yl)-5-(2,3-dichlorophenyl)pyrimidine-4- carboxamide 27

(4P)-6-amino-2-(4-amino-4- methylpiperidin-1-yl)-5-(2,3-dichlorophenyl)pyrimidine-4- carboxamide 28

2-(3-Amino-cyclohexylamino)-5- (2,3-dichloro-phenyl)-6-methyl-pyrimidine-4-carboxylic acid amide 29

6-amino-2-[4-amino-4- (hydroxymethyl)piperidin-1-yl]-5-(2,3-dichlorophenyl)pyrimidine-4- carboxamide 30

(4M)-2-(4-amino-4-methylpiperidin- 1-yl)-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carboxamide 31

(4P)-2-(4-amino-4-methylpiperidin- 1-yl)-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carboxamide 32

2-[(4-Amino-cyclohexyl)-methyl- amino]-5-(2,3-dichloro-phenyl)-6-methyl-pyrimidine-4-carboxylic acid amide 33

2-(7-Amino-3-oxa-9-aza- bicyclo[3.3.1]non-9-yl)-5-(2,3-dichloro-phenyl)-6-methyl- pyrimidine-4-carboxylic acid amide 34

6-amino-2-[8-(aminomethyl)-2-oxa- 6-azaspiro[3.4]octan-6-yl]-5-(2,3-dichlorophenyl)pyrimidine-4- carboxamide 35

2-((R)-6-Amino-2-aza-spiro[4.4]non- 2-yl)-5-(2,3-dichloro-phenyl)-6-methyl-pyrimidine-4-carboxylic acid amide 36

2-(3-Aminomethyl- cyclopentylamino)-5-(2,3-dichloro-phenyl)-6-methyl-pyrimidine-4- carboxylic acid amide 37

2-((S)-6-Amino-2-aza-spiro[4.4]non- 2-yl)-5-(2,3-dichloro-phenyl)-6-methyl-pyrimidine-4-carboxylic acid amide 38

6-amino-2-{4-amino-1-oxa-9- azaspiro[5.5]undecan-9-yl}-5-(2,3-dichlorophenyl)pyrimidine-4- carboxamide 39

6-amino-2-[4-(3-aminooxan-2- yl)piperidin-1-yl]-5-(2,3-dichlorophenyl)pyrimidine-4- carboxamide 40

6-amino-2-[3-(aminomethyl)-2-oxa- 8-azaspiro[4.5]decan-8-yl]-5-(2,3-dichlorophenyl)pyrimidine-4- carboxamide 41

6-amino-2-[4-(aminomethyl)-4- methylpiperidin-1-yl]-5-(2,3-dichlorophenyl)pyrimidine-4- carboxamide 42

2-(4-Amino-hexahydro- cyclopenta[c]pyrrol-2-yl)-5-(2,3-dichloro-phenyl)-6-methyl- pyrimidine-4-carboxylic acid amidehydrochloride 43

2-(2-Aminomethyl- cyclopentylamino)-5-(2,3-dichloro-phenyl)-6-methyl-pyrimidine-4- carboxylic acid amide 44

2-(3-Aminomethyl-3-fluoro-azetidin- 1-yl)-5-(2,3-dichloro-phenyl)-6-methyl-pyrimidine-4-carboxylic acid amide 45

2-(4-Amino-4-methyl-azepan-1-yl)- 5-(2,3-dichloro-phenyl)-6-methyl-pyrimidine-4-carboxylic acid amide 46

2-(2-Aminomethyl-azetidin-1-yl)-5- (2,3-dichloro-phenyl)-6-methyl-pyrimidine-4-carboxylic acid amide 47

(4P)-2-[(3R)-3- (aminomethyl)morpholin-4-yl]-5- (2,3-dichlorophenyl)-6-methylpyrimidine-4-carboxamide hydrochloride 48

(4P)-2-[(3S)-3- (aminomethyl)morpholin-4-yl]-5- (2,3-dichlorophenyl)-6-methylpyrimidine-4-carboxamide hydrochloride 49

6-amino-2-(4-aminoazepan-1-yl)-5- (2,3-dichlorophenyl)-pyrimidine-4-carboxamide 50

6-amino-2-(4-amino-octahydro-1H- isoindol-2-yl)-5-(2,3-dichlorophenyl)pyrimidine-4- carboxamide 51

6-amino-2-[(3R,4R)-3- (aminomethyl)-4-phenylpyrrolidin-1-yl]-5-(2,3-dichlorophenyl)pyrimidine- 4-carboxamide 52

6-amino-2-({4- azaspiro[bicyclo[2.2.2]octane-2,2′-oxan]-4′-yl}amino)-5-(2,3- dichlorophenyl)pyrimidine-4- carboxamide 53

6-amino-2-(4-amino-4- propylpiperidin-1-yl)-5-(2,3-dichloro-phenyl)pyrimidine-4-carboxamide 54

6-amino-2-[3-(aminomethyl)-3- hydroxyazetidin-1-yl]-5-(2,3-dichlorophenyl)pyrimidine-4- carboxamide 55

6-amino-2-[3-(aminomethyl)-3- methylazetidin-1-yl]-5-(2,3-dichlorophenyl)pyrimidine-4- carboxamide 56

5-(2,3-Dichloro-phenyl)-6-methyl-2- (5-methyl-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-pyrimidine-4- carboxylic acid amide 57

2-(3-Amino-3-hydroxymethyl- azetidin-1-yl)-5-(2,3-dichloro-phenyl)-6-methyl-pyrimidine-4- carboxylic acid amide 58

2-(1-Amino-5-aza-spiro[2.4]hept-5- yl)-5-(2,3-dichloro-phenyl)-6-methyl-pyrimidine-4-carboxylic acid amide 60

2-(4-Amino-4-methyl-piperidin-1-yl)- 5-(1H-benzoimidazol-4-yl)-pyrimidine-4-carboxylic acid amide 61

2-(4-Amino-4-methyl-piperidin-1-yl)- 5-benzo[1,2,5]-oxadiazol-4-yl-pyrimidine-4-carboxylic acid amide 62

6-Amino-2-(4-amino-4-methyl- piperidin-1-yl)-5-(7-chloro-1H-indazol-6-yl)-pyrimidine-4- carboxylic acid amide 63

5-(2,3-Dichloro-phenyl)-6-methyl-2- (5-methyl-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-pyrimidine-4- carboxylic acid amide 64

(5M)-6-amino-5-(2,3- dichlorophenyl)-2-{[(3S,4R)-3-fluoropiperidin-4-yl]amino}- pyrimidine-4-carboxamide 65

6-amino-2-{[(1R,2S)-2- aminocyclohexyl]amino}-5-(2,3-dichlorophenyl)-pyrimidine-4- carboxamide 66

(5P)-6-amino-2-[(3S,4S)-4-amino-3- methyl-2-oxa-8-azaspiro[4.5]decan-8-yl]-5-(2,3-dichlorophenyl)- pyrimidine-4-carboxamide 67

(5M)-6-amino-2-[(3S,4S)-4-amino- 3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl]-5-(2,3- dichlorophenyl)-pyrimidine-4-carboxamide 68

2-(3,9-Diaza-bicyclo[4.2.1]-non-3- yl)-5-(2,3-dichloro-phenyl)-6-methyl-pyrimidine-4-carboxylic acid amide 69

6-amino-2-(3-aminoazetidin-1-yl)-5- (2,3-dichlorophenyl)-pyrimidine-4-carboxamide 70

6-amino-2-[(1R,5S,6R)-6- (aminomethyl)-3-azabicyclo-[3.1.0]hexan-3-yl]-5-(2,3- dichlorophenyl)pyrimidine-4- carboxamide 71

6-amino-2-[2-(aminomethyl)- azetidin-1-yl]-5-(2,3-dichlorophenyl)pyrimidine-4- carboxamide 72

2-((3aR,4R,6aS)-4-Amino- hexahydro-cyclopenta-[c]pyrrol-2-yl)-5-(2,3-dichloro-phenyl)-6-methyl- pyrimidine-4-carboxylic acid amide73

2-((3aS,6aS)-4-Amino-hexahydro- cyclopenta-[c]pyrrol-2-yl)-5-(2,3-dichloro-phenyl)-6-methyl- pyrimidine-4-carboxylic acid amide 74

2-((3aS,4S,6aR)-4-Amino- hexahydro-cyclopenta-[c]pyrrol-2-yl)-5-(2,3-dichloro-phenyl)-6-methyl- pyrimidine-4-carboxylic acid amide75

2-((3aS,4R,6aR)-4-Amino- hexahydro-cyclopenta[c]pyrrol-2-yl)-5-(2,3-dichloro-phenyl)-6-methyl- pyrimidine-4-carboxylic acid amide 76

2-((3aR,6aR)-4-Amino-hexahydro- cyclopenta-[c]pyrrol-2-yl)-5-(2,3-dichloro-phenyl)-6-methyl- pyrimidine-4-carboxylic acid amide 77

2-((3aR,4S,6aS)-4-Amino- hexahydro-cyclopenta-[c]pyrrol-2-yl)-5-(2,3-dichloro-phenyl)-6-methyl- pyrimidine-4-carboxylic acid amide78

(4M)-2-(4-amino-4-methylpiperidin- 1-yl)-6-chloro-5-(2,3-dichlorophenyl)-pyrimidine-4- carboxamide 79

(4P)-2-(4-amino-4-methylpiperidin- 1-yl)-6-chloro-5-(2,3-dichlorophenyl)-pyrimidine-4- carboxamide 80

2-((3R,4S)-3-Amino-4-hydroxy- pyrrolidin-1-yl)-5-(2,3-dichloro-phenyl)-6-methyl-pyrimidine-4- carboxylic acid amide 81

2-(4-Amino-4-methyl-piperidin-1-yl)- 5-(2,3-dichloro-pyridin-4-yl)-6-methyl-pyrimidine-4-carboxylic acid amide 82

2-(4-Amino-4-methyl-piperidin-1-yl)- 5-(2-chloro-4-fluoro-phenyl)-6-methyl-pyrimidine-4-carboxylic acid amide 83

2-(4-Amino-4-methyl-piperidin-1-yl)- 5-(4-chloro-pyridin-3-yl)-6-methyl-pyrimidine-4-carboxylic acid amide 84

2-((3S,4S)-3-Amino-4-hydroxy- pyrrolidin-1-yl)-5-(2,3-dichloro-phenyl)-6-methyl-pyrimidine-4- carboxylic acid amide 85

2-[(3S,4S)-4-amino-3-methyl-2-oxa- 8-azaspiro[4.5]decan-8-yl]-5-(2,3-dichlorophenyl)-6-methylpyrimidine- 4-carboxamide 86

2-(4-Amino-4-methyl-piperidin-1-yl)- 6-methyl-5-pyridin-4-yl-pyrimidine-4-carboxylic acid amide 87

(4M)-2-{[(1S,3R)-3- aminocyclohexyl]amino}-5-(2,3-dichlorophenyl)-6-methylpyrimidine- 4-carboxamide 88

(4M)-2-{[(1R,3S)-3- aminocyclohexyl]amino}-5-(2,3-dichlorophenyl)-6-methylpyrimidine- 4-carboxamide 89

(4P)-2-{[(1R,3S)-3- aminocyclohexyl]amino}-5-(2,3-dichlorophenyl)-6-methylpyrimidine- 4-carboxamide 90

(4P)-2-{[(1S,3R)-3- aminocyclohexyl]amino}-5-(2,3-dichlorophenyl)-6-methylpyrimidine- 4-carboxamide 91

6-Amino-2-(4-amino-4-methyl- azepan-1-yl)-5-(2,3-dichloro-phenyl)-pyrimidine-4-carboxylic acid amide 92

2-(4-Amino-4-methyl-piperidin-1-yl)- 5-(1H-indol-3-yl)-6-methyl-pyrimidine-4-carboxylic acid amide 93

2-(4-Amino-cyclohexyl-amino)-5- (2,3-dichloro-phenyl)-6-methyl-pyrimidine-4-carboxylic acid amide 94

(5P)-2-[(3S,4S)-4-amino-3-methyl- 2-oxa-8-azaspiro[4.5]-decan-8-yl]-5-(2,3-dichloro-phenyl)-6- methylpyrimidine-4-carboxamide 95

(5M)-2-[(3S,4S)-4-amino-3-methyl- 2-oxa-8-azaspiro[4.5]-decan-8-yl]-5-(2,3-dichloro-phenyl)-6- methylpyrimidine-4-carboxamide 96

(5M)-2-[(1R)-1-amino-3,3-difluoro- 8-azaspiro[4.5]-decan-8-yl]-5-(2,3-dichloro-phenyl)-6- methylpyrimidine-4-carboxamide 97

(5P)-2-[(1R)-1-amino-3,3-difluoro-8- azaspiro[4.5]-decan-8-yl]-5-(2,3-dichlorophenyl)-6-methylpyrimidine- 4-carboxamide 98

(5P)-2-[(3aR,6aS)-3a- (aminomethyl)-octahydro-cyclopenta[c]pyrrol-2-yl]-6-amino-5- (2,3-dichlorophenyl)-pyrimidine-4-carboxamide 99

(5M)-2-[(3aR,6aS)-3a- (aminomethyl)-octahydro-cyclopenta[c]pyrrol-2-yl]-6-amino-5- (2,3-dichlorophenyl)-pyrimidine-4-carboxamide 100

(5P)-2-[(3aR,7aS)-3a- (aminomethyl)-octahydro-1H-isoindol-2-yl]-6-amino-5-(2,3- dichlorophenyl)pyrimidine-4- carboxamide101

(5P)-2-[(3aS,7aR)-3a- (aminomethyl)-octahydro-1H-isoindol-2-yl]-6-amino-5-(2,3- dichlorophenyl)pyrimidine-4- carboxamide102

(5M)-2-[(3aR,7aS)-3a- (aminomethyl)-octahydro-1H-isoindol-2-yl]-6-amino-5-(2,3- dichlorophenyl)pyrimidine-4- carboxamide103

(5M)-2-[(3aS,7aR)-3a- (aminomethyl)-octahydro-1H-isoindol-2-yl]-6-amino-5-(2,3- dichlorophenyl)pyrimidine-4- carboxamide104

(5P)-2-[(3aS,6aR)-3a- (aminomethyl)-octahydro-cyclopenta[c]pyrrol-2-yl]-6-amino-5- (2,3-dichlorophenyl)-pyrimidine-4-carboxamide 105

(5M)-2-[(3aS,6aR)-3a- (aminomethyl)-octahydro-cyclopenta[c]pyrrol-2-yl]-6-amino-5- (2,3-dichlorophenyl)-pyrimidine-4-carboxamide 106

(5P)-6-amino-2-[4-amino-4- (difluoromethyl)piperidin-1-yl]-5-(2,3-dichlorophenyl)-pyrimidine-4- carboxamide 107

(5M)-6-amino-2-[4-amino-4- (difluoromethyl)piperidin-1-yl]-5-(2,3-dichlorophenyl)-pyrimidine-4- carboxamide 108

(5P)-6-amino-2-[(4S)-4-amino-4- methylazepan-1-yl]-5-(2,3-dichlorophenyl)-pyrimidine-4- carboxamide 109

(5P)-6-amino-2-[(4R)-4-amino-4- methylazepan-1-yl]-5-(2,3-dichlorophenyl)-pyrimidine-4- carboxamide 110

(5M)-6-amino-2-[(4S)-4-amino-4- methylazepan-1-yl]-5-(2,3-dichlorophenyl)-pyrimidine-4- carboxamide 111

2-(4-Amino-4-methyl-piperidin-1-yl)- 5-(2-chloro-3-trifluoromethyl-phenyl)-6-methyl-pyrimidine-4- carboxylic acid amide 112

6-Amino-2-[(4-amino-cyclohexyl)- methyl-amino]-5-(2,3-dichloro-phenyl)-pyrimidine-4-carboxylic acid amide 113

(5P)-2-[(1R)-1-amino-8- azaspiro[4.5]decan-8-yl]-5-(2,3-dichlorophenyl)-6-methylpyrimidine- 4-carboxamide 114

(5M)-2-[(1R)-1-amino-8- azaspiro[4.5]decan-8-yl]-5-(2,3-dichlorophenyl)-6-methylpyrimidine- 4-carboxamide 115

(4M)-2-(4-amino-4-methylpiperidin-1- yl)-5-(2-chloro-4-fluoro-3-methoxyphenyl)-6-methylpyrimidine-4- carboxamide 116

(4P)-2-(4-amino-4-methylpiperidin-1- yl)-5-(2-chloro-4-fluoro-3-methoxyphenyl)-6-methylpyrimidine-4- carboxamide 117

(5P)-6-amino-2-[(1S)-1-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl]-5-(2,3-dichlorophenyl)pyrimidine-4- carboxamide 118

(5M)-6-amino-2-[(1S)-1-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl]-5-(2,3-dichlorophenyl)pyrimidine-4- carboxamide 119

(5M)-2-[(1S)-1-amino-1,3- dihydrospiro[indene-2,4′-piperidin]-1′-yl]-5-(2,3-dichlorophenyl)-6- methylpyrimidine-4-carboxamide 120

(5P)-2-[(1S)-1-amino-1,3- dihydrospiro[indene-2,4′-piperidin]-1′-yl]-5-(2,3-dichlorophenyl)-6- methylpyrimidine-4-carboxamide 121

6-amino-2-[(4S)-4-amino-4,6- dihydrospiro[cyclopenta[d][1,3]thiazole-5,4′-piperidin]-1′-yl]-5-(2,3- dichlorophenyl)pyrimidine-4- carboxamide122

2-[(3R)-3-amino-3H-spiro[1- benzofuran-2,4′-piperidin]-1′-yl]-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4- carboxamide 123

6-amino-2-[(3R)-3-amino-3H-spiro[1-benzofuran-2,4′-piperidin]-1′-yl]-5-(2,3- dichlorophenyl)pyrimidine-4-carboxamide 124

(4M)-2-[(3R)-3-amino-3H-spiro[furo[2,3-b]pyridine-2,4′-piperidin]-1′-yl]-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4- carboxamide 125

(4M)-2-[(3S)-3-amino-3H-spiro[furo[2,3-b]pyridine-2,4′-piperidin]-1′-yl]-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4- carboxamide 126

(4P)-2-[(3R)-3-amino-3H-spiro[furo[2,3-b]pyridine-2,4′-piperidin]-1′-yl]-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4- carboxamide 127

(4P)-2-[(3S)-3-amino-3H-spiro[furo[2,3-b]pyridine-2,4′-piperidin]-1′-yl]-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4- carboxamide 128

(4P)-6-amino-2-[(3R)-3-amino-3H-spiro[furo[2,3-b]pyridine-2,4′-piperidin]-1′-yl]-5-(2,3-dichlorophenyl)pyrimidine- 4-carboxamide 129

(4P)-6-amino-2-[(3S)-3-amino-3H-spiro[furo[2,3-b]pyridine-2,4′-piperidin]-1′-yl]-5-(2,3-dichlorophenyl)pyrimidine- 4-carboxamide 130

(4M)-6-amino-2-[(3R)-3-amino-3H-spiro[furo[2,3-b]pyridine-2,4′-piperidin]-1′-yl]-5-(2,3-dichlorophenyl)pyrimidine- 4-carboxamide 131

(4M)-6-amino-2-[(3S)-3-amino-3H-spiro[furo[2,3-b]pyridine-2,4′-piperidin]-1′-yl]-5-(2,3-dichlorophenyl)pyrimidine- 4-carboxamide

and pharmaceutically acceptable salts and atropisomers thereof,including mixtures thereof in all ratios.

All above-mentioned embodiments of the above definitions of thevariables, when present, of the compounds of any one of Formula I, Ia,Ib, Ic, Id, Ie and If, it should be understood in such a way that any ofthese specific embodiments can be combined with one another in anypossible embodiment in combination to give compounds of the invention.

Alkyl is a saturated unbranched or branched hydrocarbon chain and has 1,2, 3, 4, 5, 6, 7, 8, 9 or 10 C atoms. Examples of “alkyl” groups includemethyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl ortert-butyl, and the like.

Aminoalkyl is an alkyl as described above, which is substituted with an—NH₂ group.

Hydroxyalkyl is an alkyl as described above, which is substituted withan —OH group.

Alkoxy is a saturated unbranched or branched hydrocarbon chain which has1-10 C atoms, according to the formula —O(CH₂)_(n)CH₃, wherein n is 0-9.Examples of an alkoxy include methoxy, ethoxy, isopropoxy, and the like.

Cyclic alkyl or cycloalkyl is a saturated cyclic hydrocarbon chain whichhas 3-15 carbon atoms and can be in the form of a bridged ring system, amono-cyclic ring system, a bicyclic ring system and/or a spiro-connectedring system. Monocyclic cycloalkyl groups are preferably 3-7 C atoms andpreferably denotes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl orcycloheptyl. Cycloalkyl may also denote a partially unsaturated cyclicakyl, such as, for example, cyclohexenyl or cyclohexynyl. When thecycloalkyl group is a part of a bicyclic ring system, at least one ofthe rings is a 3-7 membered cycloalkyl group, which may be fused to a 5or 6 membered heteroaryl, phenyl group, a 5-7 membered heterocyclyl, ora 5-7 membered cycloalkyl group. Examples of bicyclic ring systems thatare embodied in the definition of cycloalkyl include, for example,2,3-dihydro-1H-indenyl, 4H,5H,6H-cyclopenta[d][1,3]thiazolyl,1,2,3,4-tetrahydronaphthalenyl, 5,6,7,8-tetrahydroquinolinyl,5,6,7,8-tetrahydroisoquinolinyl, 5H,6H,7H-cyclopenta(b)pyridinyl,5H,6H,7H-cyclopenta(c)pyridinyl, and the like.

Aryl, Ar or aromatic ring denotes a mono- or polycyclic aromatic orfully unsaturated cyclic hydrocarbon chain, for example unsubstitutedphenyl, naphthyl or biphenyl, furthermore preferably phenyl, naphthyl orbiphenyl, each of which is mono-, di- or trisubstituted, for example, byfluorine, chlorine, bromine, iodine, hydroxyl, methoxy, ethoxy, propoxy,butoxy, pentyloxy, hexyloxy, nitro, cyano, formyl, acetyl, propionyl,trifluoromethyl, amino, methylamino, ethylamino, dimethylamino,diethylamino, benzyloxy, sulfonamido, methylsulfonamido,ethylsulfonamido, propylsulfonamido, butylsulfonamido,dimethylsulfonamido, phenylsulfonamido, carboxyl, methoxycarbonyl,ethoxycarbonyl, and/or amidyl.

Heterocycle and heterocyclyl refer to saturated or unsaturatednon-aromatic monocyclic rings, or partially or fully non-aromatic ringsystems which may be bridged, bicylic (“fused”) and/or spiro-connected.Heterocyclyls contain at least one heteroatom selected from O, S and N,and further may include the oxidized forms of sulfur, namely SO and SO₂.Monocyclic heterocyclyl groups are preferably 3-7 atoms and includesazetidine, tetrahydrofuran (THF), dihydrofuran, 1,4-dioxane, morpholine,1,4-dithiane, piperazine, piperidine, 1,3-dioxolane, imidazolidine,imidazoline, pyrroline, pyrrolidine, tetrahydropyran, dihydropyran,oxathiolane, dithiolane, 1,3-dioxane, 1,3-dithiane, oxathiane,thiomorpholine, oxolane, oxane, azepane, and the like. When theheterocyclyl group is a part of a bicyclic ring system, at least one ofthe rings is a 3-7 membered heterocyclic group, which may be fused to a5 or 6 membered heteroaryl, phenyl group, a 5-7 membered heterocyclyl,or a 5-7 membered cycloalkyl group. Examples of bicyclic ring systemsthat are embodied in the definition of heterocyclyl include, forexample, 2H,3H-furo[2,3-b]pyridine, 2H,3H-furo[2,3-c]pyridine,2H,3H-furo[2,3-d]pyridine, 2,3-dihydrobenzofuran,octahydro-1H-isoindole, octahydrocyclopenta[c]pyrrole,octahydropyrrolo[3,4-c]pyrrole, 3-azabicyclo[3.1.0]hexane,3,9-diazabicyclo[4.2.1]non-3-yl, and the like.

Heteroaryl means an aromatic or partially aromatic heterocycle thatcontains at least one ring heteroatom selected from O, S and N.Heteroaryls thus includes heteroaryls fused to other kinds of rings,such as aryls, cycloalkyls and heterocycles that are not aromatic.Examples of heteroaryl groups include: pyrrolyl, isoxazolyl,isothiazolyl, pyrazolyl, pyridyl, oxazolyl, oxadiazolyl, thiadiazolyl,thiazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, triazinyl,thienyl, pyrimidyl, benzisoxazolyl, benzoxazolyl, benzothiazolyl,benzothiadiazolyl, dihydrobenzofuranyl, indolinyl, pyridazinyl,indazolyl, isoxazolyl, isoindolyl, dihydrobenzothienyl, indolizinyl,cinnolinyl, phthalazinyl, quinazolinyl, naphthyridinyl, carbazolyl,benzdioxinyl, benzodioxolyl, quinoxalinyl, purinyl, furazanyl,thiophenyl, isobenzylfuranyl, benzimidazolyl, benzofuranyl,benzothienyl, quinolyl, indolyl, isoquinolyl, dibenzofuranyl, and thelike. For heterocyclyl and heteroaryl groups, rings and ring systemscontaining from 3-15 atoms are included, forming 1-3 rings.

Spiro connected cyclic moieties denote those in which two rings, or ringsystems, are connected through a single, common, carbon atom. Spirocompounds may be fully carbocyclic (all carbon) or heterocyclic (havingone or more non-carbon atom). Spiro connected cyclic moieties whichinclude two cycles are considered bicyclic; spiro connected cyclicmoieties which connect a monocycle with a bicyclic moiety are consideredtricyclic moieties. Examples of spiro connected bicyclic moietiesinclude 8-azaspiro[4.5]decane, 2-oxa-8-azaspiro[4.5]decane,2-azaspiro[3.4]octane, 6-azaspiro[3.4]octane,2-oxa-6-azaspiro[3.4]octane, 2-azaspiro[4.4]nonane,1-oxa-9-azaspiro[5.5]undecane, 5-azaspiro[2.4]heptane,1,3-dihydrospiro-[indene-2,4′-piperidine],5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′-piperidine],3H-spiro[furo[2,3-b]pyridine-2,4′-piperidine],3H-spiro[1-benzofuran-2,4′-piperidine],4,6-dihydrospiro[cyclopenta[d][1,3]thiazole-5,4′-piperidine], and thelike.

Compounds of the present invention may form atropisomers, which areconformational isomers in relation to the pyrimidine moiety present inFormulae I, Ia, Ib, Ic, Id, Ie and If. Atropisomers are stereoisomersarising because of hindered rotation about a single bond, where energydifferences due to steric strain or other contributors create a barrierto rotation that is high enough to allow for isolation of individualconformers. There are two different atropisomers that were observed inthe compounds of the present invention, which are shown, for examplebelow when R2 is a phenyl substituted with R6, R7 and R8:

These forms are denoted in the nomenclature of the compounds as being ofthe M or P forms, depending on the orientation of the aryl or heteroarylgroup and the substituent R3 on the pyrimidine ring. Examples of the Mand P forms are provided in the examples. Particularly preferredcompounds are those with the orientation:

The invention also relates to a pharmaceutical preparation comprisingthe compound according to the present invention and/or one of itsphysiologically acceptable salts.

The invention also relates to a pharmaceutical preparation according tothe invention of this type, comprising further excipients and/oradjuvants.

In addition, the invention relates to an above pharmaceuticalpreparation according to the invention, further comprising one or moreadditional therapeutic agent.

The compound of the present invention can be used in its freebase form.On the other hand, the present invention also encompasses the use of thecompounds of the present invention in the form of their pharmaceuticallyacceptable salts, which can be derived from various organic andinorganic bases by procedures known in the art. The term pharmaceuticalsalt is used to refer to an ionisable drug that has been combined with acounter-ion to form a neutral complex. Converting a drug into a saltthrough this process can increase its chemical stability, render thecomplex easier to administer and allow manipulation of the agent'spharmacokinetic profile. Salt selection is now a common standardoperation performed with small ionisable molecules during drugdevelopment, and in many cases the drug salts display preferentialproperties as compared with the parent molecule. Pharmaceuticallyacceptable salt forms of the compounds of the present invention are forthe most part prepared by conventional methods.

In one embodiment, the pharmaceutically acceptable salt of the compoundof the invention may be selected from hydrochloride, sodium, sulfate,acetate, phosphate or diphosphate, chloride, potassium, maleate,calcium, citrate, mesylate, nitrate, tartrate, aluminium, gluconate,benzoate, besylate, and edisylate. In one aspect of this embodiment, thepharmaceutically acceptable salt is benzoate, besylate, or edisylate.

A pharmaceutically acceptable salt of the compound of the presentinvention includes solvates of said salts. The term solvate is taken tomean adductions of inert solvent molecules of the compounds of thepresent invention which form owing to their mutual attractive force.Solvates are, for example, hydrates, such as monohydrates or dihydrates,or alcoholates, i.e. addition compounds with alcohols, such as, forexample, with methanol or ethanol.

Compounds of the general formula I may contain one or more centres ofchirality, so that all stereoisomers, enantiomers, diastereomers, etc.,of the compounds of the general formula I are also claimed in thepresent invention Thus, the invention also relates to the opticallyactive forms (stereoisomers), the enantiomers, the racemates, thediastereomers and hydrates and solvates of these compounds.

It is furthermore intended that a compound of the formula I includesisotope-labelled forms thereof. An isotope-labelled form of a compoundof the formula I is identical to this compound apart from the fact thatone or more atoms of the compound have been replaced by an atom or atomshaving an atomic mass or mass number which differs from the atomic massor mass number of the atom which usually occurs naturally. Examples ofisotopes which are readily commercially available and which can beincorporated into a compound of the formula I by well-known methodsinclude isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus,fluorine and chlorine, for example ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P,³²P, ³⁵S, ¹⁸F and ³⁶Cl, respectively. A compound of the formula I, or apharmaceutically acceptable salt thereof, which contains one or more ofthe above-mentioned isotopes and/or other isotopes of other atoms isintended to be part of the present invention. An isotope-labelledcompound of the formula I can be used in a number of beneficial ways.For example, an isotope-labelled compound of the formula I into which,for example, a radioisotope, such as ³H or ¹⁴C, has been incorporated issuitable for medicament and/or substrate tissue distribution assays.These radioisotopes, i.e. tritium (³H) and carbon-14 (¹⁴C), areparticularly preferred owing to their simple preparation and excellentdetectability. Incorporation of heavier isotopes, for example deuterium(²H), into a compound of the formula I has therapeutic advantages owingto the higher metabolic stability of this isotope-labelled compound.Higher metabolic stability translates directly into an increased in-vivohalf-life or lower dosages, which under most circumstances wouldrepresent a preferred embodiment of the present invention. Anisotope-labelled compound of the formula I can usually be prepared bycarrying out the procedures disclosed in the synthesis schemes and therelated description, in the example part and in the preparation part inthe present text, replacing a non-isotope-labelled reactant with areadily available isotope-labelled reactant.

In order to manipulate the oxidative metabolism of the compound by wayof the primary kinetic isotope effect, deuterium (²H) can also beincorporated into a compound of the formula I. The primary kineticisotope effect is a change in the rate of a chemical reaction thatresults from exchange of isotopic nuclei, which in turn is caused by thechange in ground state energies necessary for covalent bond forma-tionafter this isotopic exchange. Exchange of a heavier isotope usuallyresults in a lowering of the ground state energy for a chemical bond andthus causes a reduction in the rate in rate-limiting bond breakage. Ifthe bond breakage occurs in or in the vicinity of a saddle-point regionalong the coordinate of a multi-product reaction, the productdistribution ratios can be altered substantially. For explanation: ifdeuterium is bonded to a carbon atom in a non-exchangeable position,rate differences of k_(M)/k_(D)=2-7 are typical. If this rate differenceis successfully applied to a compound of the formula I that issusceptible to oxidation, the profile of this compound in vivo canthereby be drastically modified and result in improved pharmacokineticproperties.

The replacement of hydrogen by deuterium in a compound of the formula Ican also be used to achieve a favourable modification of the metabolitespectrum of the starting compound in order to diminish or eliminateundesired toxic metabolites. For example, if a toxic metabolite arisesthrough oxidative carbon-hydrogen (C—H) bond cleavage, it can reasonablybe assumed that the deuterated analogue will greatly diminish oreliminate production of the undesired metabolite, even if the particularoxidation is not a rate-determining step. Further information on thestate of the art with respect to deuterium-hydrogen exchange is given,for example in Hanzlik et al., J. Org. Chem. 55, 3992-3997, 1990, Reideret al., J. Org. Chem. 52, 3326-3334, 1987, Foster, Adv. Drug Res. 14,1-40, 1985, Gillette et al., Biochemistry 33(10), 2927-2937, 1994, andJarman et al., Carcinogenesis 16(4), 683-688, 1993.

The invention also relates to mixtures of the compounds of the formula Iaccording to the invention, for example mixtures of two atropisomersand/or two or more diastereomers, for example in the ratio 1:1, 1:2,1:3, 1:4, 1:5, 1:10, 1:100 or 1:1000. These are particularly preferablymixtures of two stereoisomeric compounds. In one embodiment of thepresent invention, mixtures of atropisomers and/or diastereomers containat least 80% of the desired conformation. In one aspect of thisembodiment, the mixture of atropisomers and/or diastereomers contain atleast 85% of the desired conformation. In another aspect of thisembodiment, the mixture of atropisomers and/or diastereomers contain atleast 90% of the desired conformation. In one aspect of this embodiment,the mixture of atropisomers and/or diastereomers contain at least 95% ofthe desired conformation. In one aspect of this embodiment, the mixtureof atropisomers and/or diastereomers contain at least 98% of the desiredconformation.

If desired, the starting materials can also be formed in situ by notisolating them from the reaction mixture, but instead immediatelyconverting them further into the compounds of the formula I.

The compounds of the formula I are preferably obtained by liberatingthem from their functional derivatives by solvolysis, in particular byhydrolysis, or by hydrogenolysis. Preferred starting materials for thesolvolysis or hydrogenolysis are those which contain correspondinglyprotected amino, carboxyl and/or hydroxyl groups instead of one or morefree amino, carboxyl and/or hydroxyl groups, preferably those whichcarry an amino-protecting group instead of an H atom which is connectedto an N atom. Preference is furthermore given to starting materialswhich carry a hydroxyl-protecting group instead of the H atom of ahydroxyl group. Preference is also given to starting materials whichcarry a protected carboxyl group instead of a free carboxyl group. It isalso possible for a plurality of identical or different protected amino,carboxyl and/or hydroxyl groups to be present in the molecule of thestarting material. If the protecting groups present are different fromone another, they can in many cases be cleaved off selectively.

The term “amino-protecting group” is generally known and relates togroups which are suitable for protecting (blocking) an amino groupagainst chemical reactions, but which can easily be removed after thedesired chemical reaction has been carried out elsewhere in themolecule. Typical of such groups are, in particular, unsubstituted orsubstituted acyl groups, furthermore unsubstituted or substituted aryl(for example 2,4-dinitophenyl) or aralkyl groups (for example benzyl,4-nitrobenzyl, triphenylmethyl). Since the amino-protecting groups areremoved after the desired reaction or reaction sequence, their type andsize is, in addition, not crucial, but preference is given to thosehaving 1-20, in particular 1-8, C atoms. The term “acyl group” is to beunderstood in the broadest sense in connection with the present process.It encompasses acyl groups derived from aliphatic, araliphatic, aromaticor heterocyclic carboxylic acids or sulfonic acids and, in particular,alkoxy-carbonyl, aryloxycarbonyl and especially aralkoxycarbonyl groups.Examples of such acyl groups are alkanoyl, such as acteyl, propionyl,buturyl, aralkanoyl, such as phenylacetyl, aroyl, such as benzoyl ortoluyl, aryoxyaklkanoyl, such as phenoxyacetyl, alkyoxycarbonyyl, suchas methoxycarbonyl, ethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, BOC,2-iodoethoxycaronyl, aralkoxycarbonyl. such as CBZ,4-methoxybenzyloxycarbonyl or FMOC. Preferred acyl groups are CBZ, FMOC,benzyl and acetyl.

The term “acid-protecting group” or “carboxyl-protecting group” islikewise generally known and relates to groups which are suitable forprotecting a —COOH group against chemical reactions, but which caneasily be removed after the desired chemical reaction has been carriedout elsewhere in the molecule. The use of esters instead of the freeacids, for example of substituted and unsubstituted alkyl esters (suchas methyl, ethyl, tert-butyl and substituted derivatives thereof), ofsubstituted and unsubstituted benzyl esters or silyl esters, is typical.The type and size of the acid-protecting groups is not crucial, butpreference is given to those having 1-20, in particular 1-10, C atoms.

The term “hydroxyl-protecting group” is likewise generally known andrelates to groups which are suitable for protecting a hydroxyl groupagainst chemical reactions, but which can easily be removed after thedesired chemical reaction has been carried out elsewhere in themolecule. Typical of such groups are the above-mentioned unsubstitutedor substituted aryl, aralkyl or acyl groups, furthermore also alkylgroups. Their type and size of the hydroxyl-protecting groups is notcrucial, but preference is given to those having 1-20, in particular1-10, C atoms. Examples of hydroxyl-protecting groups are, inter alia,benzyl, p-nitrobenzoyl, p-toluenesulfonyl and acetyl, where benzyl andacetyl are preferred.

Further typical examples of amino-, acid- and hydroxyl-protecting groupsare found, for example, in “Greene's Protective Groups in OrganicSynthesis”, fourth edition, Wiley-Interscience, 2007.

The resultant compounds according to the invention can be separated fromthe corresponding solution in which they are prepared (for example bycentrifugation and washing) and can be stored in another compositionafter separation, or they can remain directly in the preparationsolution. The resultant compounds according to the invention can also betaken up in desired solvents for the particular use.

Conventional work-up steps, such as, for example, addition of water tothe reaction mixture and extraction, enable the compounds to be obtainedafter removal of the solvent. It may be advantageous, for furtherpurification of the product, to follow this with a distillation orcrystallisation or to carry out a chromatographic purification.

It has been surprisingly found that the compounds of the formula I mayhave advantageous efficacy, selectivity, pharmacokinetic properties,dosing schedule, lower toxicity, and/or physical properties as comparedto prior art compounds.

The invention furthermore relates to the use of compounds according tothe invention for the preparation of a medicament for the treatment ofdiseases which are caused, promoted and/or propagated by SHP2 or itsagonists.

The invention thus also relates, in particular, to a medicamentcomprising at least one compound according to the invention and/or oneof its pharmaceutically acceptable salts, for use in the treatment ofphysiological and/or pathophysiological states. Particular preference isgiven, in particular, to physiological and/or pathophysiological stateswhich are connected to SHP2. Physiological and/or pathophysiologicalstates are taken to mean physiological and/or pathophysiological stateswhich are medically relevant, such as, for example, diseases orillnesses and medical disorders, complaints, symptoms or complicationsand the like, in particular diseases.

The invention furthermore relates to a medicament comprising at leastone compound according to the invention and/or one of itspharmaceutically acceptable salts, for use in the treatment ofphysiological and/or pathophysiological states selected from the groupconsisting of hyperproliferative diseases and disorders. in oneembodiment, the hyperproliferative disease or disorder is cancer.

The invention thus particularly relates to a medicament comprising atleast one compound according to the invention and/or one of itspharmaceutically acceptable salts, wherein the cancer is selected fromthe group consisting of acute and chronic lymphocytic leukemia, acutegranulocytic leukemia, adrenal cortex cancer, bladder cancer, braincancer, breast cancer, cervical cancer, cervical hyperplasia, choriocancer, colon cancer, endometrial cancer, esophageal cancer, essentialthrombocytosis, genitourinary carcinoma, glioma, glioblastoma, hairycell leukemia, head and neck carcinoma, Hodgkin's disease, Kaposi'ssarcoma, lung carcinoma, lymphoma, malignant carcinoid carcinoma,malignant hypercalcemia, malignant melanoma, malignant pancreaticinsulinoma, medullary thyroid carcinoma, melanoma, multiple myeloma,mycosis fungoides, myeloid and lymphocytic leukemia, neuroblastoma,non-Hodgkin's lymphoma, non-small cell lung cancer, osteogenic sarcoma,ovarian carcinoma, pancreatic carcinoma, polycythemia vera, primarybrain carcinoma, primary macroglobulinemia, prostatic cancer, renal cellcancer, rhabdomyosarcoma, skin cancer, small-cell lung cancer,soft-tissue sarcoma, squamous cell cancer, stomach cancer, testicularcancer, thyroid cancer and Wilms' tumor. In one embodiment of theinvention, the cancer is selected from non-small cell lung cancer, smallcell lung cancer, head and neck carcinoma, breast cancer, esophagealcancer, gastric cancer, colorectal cancer, glioblastoma, pancreaticcancer, osteosarcoma, melanoma and kidney cancer. In one aspect of thisembodiment, the cancer is head and neck carcinoma. In another aspect ofthis embodiment, the cancer is lung cancer. In one aspect of thisembodiment, the lung cancer is non-small cell lung cancer. In anotheraspect of this embodiment, the lung cancer is small cell lung cancer. Inanother aspect of this embodiment, the cancer is colorectal cancer. In afurther aspect of this embodiment, the cancer is esophageal cancer. Inanother aspect of this embodiment, the cancer is gastric cancer.

The invention further relates to a medicament comprising at least onecompound according to the invention and/or one of its pharmaceuticallyacceptable salts, for use in the treatment of physiological and/orpathophysiological states selected from the group consisting ofhyperproliferative and infectious diseases and disorders, wherein thehyperproliferative disease or disorder is selected from the groupconsisting of age-related macular degeneration, Crohn's disease,cirrhosis, chronic inflammatory-related disorders, proliferativediabetic retinopathy, proliferative vitreoretinopathy, retinopathy ofprematurity, granulomatosis, immune hyperproliferation associated withorgan or tissue transplantation and an immunoproliferative disease ordisorder selected from the group consisting of inflammatory boweldisease, psoriasis, rheumatoid arthritis, systemic lupus erythematosus(SLE), vascular hyperproliferation secondary to retinal hypoxia andvasculitis.

It is intended that the medicaments disclosed above include acorresponding use of the compounds according to the invention for thepreparation of a medicament for the treatment of the above physiologicaland/or pathophysiological states.

It is additionally intended that the medicaments disclosed above includea corresponding method for the treatment of the above physiologicaland/or pathophysiological states in which at least one compoundaccording to the invention is administered to a patient in need of sucha treatment.

The compounds according to the invention preferably exhibit anadvantageous biological activity which can easily be demonstrated inenzyme assays and animal experiments, as described in the examples. Insuch enzyme-based assays, the compounds according to the inventionpreferably exhibit and cause an inhibiting effect, which is usuallydocumented by IC₅₀ values in a suitable range, preferably in themicromolar range and more preferably in the nanomolar range.

The compounds according to the invention can be administered to humansor animals, in particular mammals, such as apes, dogs, cats, rats ormice, and can be used in the therapeutic treatment of the human oranimal body and in the combating of the above-mentioned diseases. Theycan furthermore be used as diagnostic agents or as reagents.

Furthermore, compounds according to the invention can be used for theisolation and investigation of the activity or expression of SHP2. Inaddition, they are particularly suitable for use in diagnostic methodsfor diseases in connection with disturbed SHP2 activity. The inventiontherefore furthermore relates to the use of the compounds according tothe invention for the isolation and investigation of the activity orexpression of SHP2 or as binders and inhibitors of SHP2.

For diagnostic purposes, the compounds according to the invention can,for example, be radioactively labelled. Examples of radioactive labelsare ³H, ¹⁴C, ²³¹I and ¹²⁵I. A preferred labelling method is the iodogenmethod (Fraker et al., 1978). In addition, the compounds according tothe invention can be labelled by enzymes, fluorophores and chemophores.Examples of enzymes are alkaline phosphatase, p-galactosidase andglucose oxidase, an example of a fluorophore is fluorescein, an exampleof a chemophore is luminol, and automated detection systems, for examplefor fluorescent colorations, are described, for example, in U.S. Pat.Nos. 4,125,828 and 4,207,554.

The invention therefore furthermore relates to pharmaceuticalpreparations comprising at least one compound of the formula I and/orpharmaceutically acceptable salts thereof. In particular, the inventionalso relates to pharmaceutical preparations which comprise furtherexcipients and/or adjuvants, and also to pharmaceutical preparationswhich comprise at least one further medicament active compound.

In particular, the invention also relates to a process for thepreparation of a pharmaceutical preparation, characterised in that acompound of the formula I and/or one of its pharmaceutically acceptablesalts, is brought into a suitable dosage form together with a solid,liquid or semi-liquid excipient or adjuvant and optionally with one ormore additional therapeutic agent.

The pharmaceutical preparations according to the invention can be usedas medicaments in human or veterinary medicine. The patient or host canbelong to any mammal species, for example a primate species,particularly humans; rodents, including mice, rats and hamsters;rabbits; horses, cattle, dogs, cats, etc. Animal models are of interestfor experimental investigations, where they provide a model for thetreatment of a human disease.

Suitable carrier substances are organic or inorganic substances whichare suitable for enteral (for example oral), parenteral or topicaladministration and do not react with the novel compounds, for examplewater, vegetable oils (such as sunflower oil or cod-liver oil), benzylalcohols, polyethylene glycols, gelatine, carbohydrates, such as lactoseor starch, magnesium stearate, talc, lanolin or Vaseline. Owing to hisexpert knowledge, the person skilled in the art is familiar with whichadjuvants are suitable for the desired medicament formulation. Besidessolvents, for example water, physiological saline solution or alcohols,such as, for example, ethanol, propanol or glycerol, sugar solutions,such as glucose or mannitol solutions, or a mixture of the saidsolvents, gel formers, tablet assistants and other active-ingredientcarriers, it is also possible to use, for example, lubricants,stabilisers and/or wetting agents, emulsifiers, salts for influencingthe osmotic pressure, anti-oxidants, dispersants, antifoams, buffersubstances, flavours and/or aromas or flavour correctants,preservatives, solubilisers or dyes. If desired, preparations ormedicaments according to the invention may comprise one or more furtheractive compounds, for example one or more vitamins.

If desired, preparations or medicaments according to the invention maycomprise one or more further active compounds and/or one or more actionenhancers (adjuvants).

The terms “pharmaceutical formulation” and “pharmaceutical preparation”are used as synonyms for the purposes of the present invention.

As used here, “pharmaceutically acceptable” relates to medicaments,precipitation reagents, excipients, adjuvants, stabilisers, solvents andother agents which facilitate the administration of the pharmaceuticalpreparations obtained therefrom to a mammal without undesiredphysiological side effects, such as, for example, nausea, dizziness,digestion problems or the like.

In pharmaceutical preparations for parenteral administration, there is arequirement for isotonicity, euhydration and tolerability and safety ofthe formulation (low toxicity), of the adjuvants employed and of theprimary packaging. Surprisingly, the compounds according to theinvention preferably have the advantage that direct use is possible andfurther purification steps for the removal of toxicologicallyunacceptable agents, such as, for example, high concentrations oforganic solvents or other toxicologically unacceptable adjuvants, arethus unnecessary before use of the compounds according to the inventionin pharmaceutical formulations.

The invention particularly preferably also relates to pharmaceuticalpreparations comprising at least one compound according to the inventionin precipitated non-crystalline, precipitated crystalline or indissolved or suspended form, and optionally excipients and/or adjuvantsand/or further pharmaceutical active compounds.

The compounds according to the invention preferably enable thepreparation of highly concentrated formulations without unfavourable,undesired aggregation of the compounds according to the inventionoccurring. Thus, ready-to-use solutions having a high active-ingredientcontent can be prepared with the aid of compounds according to theinvention with aqueous solvents or in aqueous media.

The compounds and/or physiologically acceptable salts and solvatesthereof can also be lyophilised and the resultant lyophilisates used,for example, for the preparation of injection preparations.

Pharmaceutical preparations according to the invention may also comprisemixtures of a plurality of compounds according to the invention.

The preparations according to the invention are physiologically welltolerated, easy to prepare, can be dispensed precisely and arepreferably stable with respect to assay, decomposition products andaggregates throughout storage and transport and during multiple freezingand thawing processes. They can preferably be stored in a stable mannerover a period of at least three months to two years at refrigeratortemperature (2-8° C.) and at room temperature (23-27° C.) and 60%relative atmospheric humidity (R.H.).

For example, the compounds according to the invention can be stored in astable manner by drying and when necessary converted into a ready-to-usepharmaceutical preparation by dissolution or suspension. Possible dryingmethods are, for example, without being restricted to these examples,nitrogen-gas drying, vacuum-oven drying, lyophilisation, washing withorganic solvents and subsequent air drying, liquid-bed drying,fluidised-bed drying, spray drying, roller drying, layer drying, airdrying at room temperature and further methods.

The term “effective amount” denotes the amount of a compound of FormulaI, or a pharmaceutically acceptable salt thereof, which causes in atissue, system, animal or human a biological or medical response whichis sought or desired, for example, by a researcher or physician.

In addition, the term “therapeutically effective amount” denotes anamount which, compared with a corresponding subject who has not receivedthis amount, has the following consequence: improvement of one or moresymptoms, healing, or elimination of a disease, syndrome, disease state,complaint, disorder or prevention of side effects. “Therapeuticallyeffective amount” also encompasses a reduction in the progress of adisease, complaint or disorder. In the context of cancer treatment, a“therapeutically effective amount” can lead to lessening the tumorburden of a subject, delaying the progression of disease(“progression-free survival”), prolonging the life expectancy of thesubject (improving the overall survival), slowing or preventing themetastasis of the primary tumor to other tissues and/or improving thequality of life of the subject undergoing treatment. The term“therapeutically effective amount” also encompasses the amounts whichare effective for increasing normal physiological function.

One embodiment of the present invention is the use of preparations ormedicaments consisting of compounds according to the invention, and/orpharmaceutically acceptable salts thereof, for preparations in dosagesof between 0.1 and 500 mg, in particular 1 and 300 mg, per use unit. Thedaily dose is preferably between 0.001 and 250 mg/kg, in particular 0.01and 100 mg/kg, of body weight. The preparation can be administered oneor more times per day, for example two, three or four times per day.However, the individual dose for a patient depends on a large number ofindividual factors, such as, for example, on the efficacy of theparticular compound used, on the age, body weight, general state ofhealth, sex, nutrition, on the time and method of administration, on theexcretion rate, on the combination with other medicaments and on theseverity and duration of the particular disease.

A measure of the uptake of a medicament active compound in an organismis its bioavailability. If the medicament active compound is deliveredto the organism intravenously in the form of an injection solution, itsabsolute bioavailability, i.e. the proportion of the pharmaceuticalwhich reaches the systemic blood, i.e. the major circulation, inunchanged form, is 100%. In the case of oral administration of atherapeutic active compound, the active compound is generally in theform of a solid in the formulation and must therefore first be dissolvedin order that it is able to overcome the entry barriers, for example thegastrointestinal tract, the oral mucous membrane, nasal membranes or theskin, in particular the stratum corneum, or can be absorbed by the body.Data on the pharmacokinetics, i.e. on the bioavailability, can beobtained analogously to the method of J. Shaffer et al., J. Pharm.Sciences, 88 (1999), 313-318.

Furthermore, medicaments of this type can be prepared by means of one ofthe processes generally known in the pharmaceutical art.

Medicaments can be adapted for administration via any desired suitableroute, for example by the oral (including buccal or sublingual), rectal,pulmonary, nasal, topical (including buccal, sublingual or transdermal),vaginal or parenteral (including subcutaneous, intramuscular,intravenous, intradermal and in particular intra-articular) routes.Medicaments of this type can be prepared by means of all processes knownin the pharmaceutical art by, for example, combining the active compoundwith the excipient(s) or adjuvant(s).

Suitable for enteral administration (oral or rectal) are, in particular,tablets, dragees, capsules, syrups, juices, drops or suppositories, andsuitable for topical use are ointments, creams, pastes, lotions, gels,sprays, foams, aerosols, solutions (for example solutions in alcohols,such as ethanol or isopropanol, acetonitrile, DMF, dimethylacetamide,1,2-propanediol or mixtures thereof with one another and/or with water)or powders. Also, particularly suitable for topical uses are liposomalpreparations.

It goes without saying that, besides the constituents particularlymentioned above, the medicaments according to the invention may alsocomprise other agents usual in the art with respect to the particulartype of pharmaceutical formulation.

The invention also relates to a set (kit) consisting of separate packsof

-   -   a) an effective amount of a compound of the formula I and/or        physiologically acceptable salts, derivatives, solvates,        prodrugs, stereoisomers and atropisomers thereof, including        mixtures thereof in all ratios, and    -   b) an effective amount of a further medicament active compound.

The set comprises suitable containers, such as boxes or cartons,individual bottles, bags or ampoules. The set may, for example, compriseseparate ampoules each containing an effective amount of a compound ofthe formula I and/or pharmaceutically acceptable salts thereof, and aneffective amount of one or more additional therapeutic agents indissolved or lyophilised form.

Furthermore, the medicaments according to the invention can be used inorder to provide additive or synergistic effects in certain knowntherapies and/or can be used in order to restore the efficacy of certainexisting therapies.

Besides the compounds according to the invention, the pharmaceuticalpreparations according to the invention may also comprise one or moreadditional therapeutic agents, for example for use in the treatment ofcancer, other anti-tumor medicaments. For the treatment of the otherdiseases mentioned, the pharmaceutical preparations according to theinvention may also, besides the compounds according to the invention,comprise further medicament active compounds which are known to theperson skilled in the art in the treatment thereof.

In one embodiment, a compound of the present invention, or apharmaceutically acceptable salt thereof, is administered in combinationwith one or more additional therapeutic agent. In one aspect of thisinvention, the one or more additional therapeutic agent is an EGFRinhibitor, MET inhibitor, PD-L1 inhibitor, MEK 1/2 inhibitor, TGF-βRpathway inhibitor, or a combination thereof. In another aspect of thisembodiment, the one or more additional therapeutic agent is Erbitux,tepotinib, avelumab, Muc1-TGFβR2 Nb, EGFR-Muc1-ADC, pimasertib,pembrolizumab, nivolumab, cemiplimab, atezolizumab, durvalumab, or acombination thereof. In one aspect of this embodiment, the one or moreadditional therapeutic agents is Erbitux, tepotinib, avelumab,pimasertib or a combination thereof.

In one principal embodiment, methods are provided for enhancing animmune response in a host in need thereof. The immune response can beenhanced by reducing T cell tolerance, including by increasing IFN-γrelease, by decreasing regulatory T cell production or activation, or byincreasing antigen-specific memory T cell production in a host. In oneembodiment, the method comprises administering a compound of the presentinvention to a host in combination or alternation with an antibody. Inone aspect of this embodiment, the antibody is a therapeutic antibody.In one particular embodiment, a method of enhancing efficacy of passiveantibody therapy is provided comprising administering a compound of thepresent invention in combination or alternation with one or more passiveantibodies. This method can enhance the efficacy of antibody therapy fortreatment of abnormal cell proliferative disorders such as cancer or canenhance the efficacy of therapy in the treatment or prevention ofinfectious diseases. The compound of the present invention can beadministered in combination or alternation with antibodies such asrituximab, herceptin or erbitux, for example.

In another principal embodiment, a method of treating or preventingabnormal cell proliferation is provided comprising administering acompound of the present invention to a host in need thereofsubstantially in the absence of another anti-cancer agent.

In another principal embodiment, a method of treating or preventingabnormal cell proliferation in a host in need thereof is provided,comprising administering a first a compound of the present inventionsubstantially in combination with a first anti-cancer agent to the hostand subsequently administering a second SHP2 antagonist. In one aspectof this embodiment, the second antagonist is administered substantiallyin the absence of another anti-cancer agent. In another principalembodiment, a method of treating or preventing abnormal cellproliferation in a host in need thereof is provided, comprisingadministering a compound of the present invention substantially incombination with a first anti-cancer agent to the host and subsequentlyadministering a second anti-cancer agent in the absence of theantagonist.

Thus, the cancer treatment disclosed here can be carried out as therapywith a compound of the present invention or in combination with anoperation, irradiation or chemotherapy. Chemotherapy of this type caninclude the use of one or more additional therapeutic agents selectedfrom the group consisting of:

(i) antiproliferative/antineoplastic/DNA-damaging active compounds andcombi-nations thereof, as used in medical oncology, such as alkylatingactive compounds (for example cis-platin, parboplatin, cyclophosphamide,nitrogen mustard, melphalan, chlorambucil, busulphan and nitrosoureas);antimetabolites (for example antifolates such as fluoropyrimidines suchas 5-fluorouracil and tegafur, raltitrexed, methotrexate, cytosinearabinoside, hydroxyurea and gemcitabine); antitumour antibiotics (forexample anthracyclines, such as adriamycin, bleomycin, doxorubicin,daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin andmithramycin); antimitotic active compounds (for example vinca alkaloids,such as vincristine, vin-blastine, vindesine and vinorelbine, andtaxoids, such as taxol and taxotere); topoisomerase inhibitors (forexample epipodophyllotoxins, such as etoposide and teniposide,amsacrine, topotecan, irinotecan and camptothecin) andcell-differentiating active compounds (for example all-trans-retinoicacid, 13-cis-retinoic acid and fenretinide);

(ii) cytostatic active compounds, such as anti-oestrogens (for exampletamoxifen, toremifene, raloxifene, droloxifene and iodoxyfene),oestrogen receptor regulators (for example fulvestrant), anti-androgens(for example bicalutamide, flutamide, nilutamide and cyproteroneacetate), LHRH antagonists or LHRH agonists (for example goserelin,leuprorelin and buserelin), progesterones (for example megestrolacetate), aromatase inhibitors (for example anastrozole, letrozole,vorazole and exemestane) and inhibitors of 5α-reductase, such asfinasteride;

(iii) active compounds which inhibit cancer invasion including forexample metallo-proteinase inhibitors, like marimastat, and inhibitorsof urokinase plasminogen activator receptor function;

(iv) inhibitors of growth factor function, for example growth factorantibodies, growth factor receptor antibodies, for example theanti-erbb2 antibody trastuzumab [Herceptin™] and the anti-erbb1 antibodycetuximab [C225]), farnesyl transferase inhibitors, tyrosine kinaseinhibitors and serine/threonine kinase inhibitors, for exampleinhibitors of the epidermal growth factor family (for example EGFRfamily tyrosine kinase inhibitors, such asN-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-amine (gefitinib, AZD1839), N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine (erlotinib, OSI-774) and6-acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)quinazolin-4-amine(Cl 1033), for example inhibitors of the platelet-derived growth factorfamily and, for example, inhibitors of the hepatocyte growth factorfamily;

(v) anti-angiogenic active compounds, such as bevacizumab, angiostatin,endostatin, linomide, batimastat, captopril, cartilage derivedinhibitor, genistein, interleukin 12, lavendustin, medroxypregesteroneacetate, recombinant human platelet factor 4, tecogalan, thrombospondin,TNP-470, anti-VEGF monoclonal antibody, soluble VEGF-receptor chimaericprotein, anti-VEGF receptor antibodies, anti-PDGF receptors, inhibitorsof integrins, tyrosine kinase inhibitors, serine/threonine kinaseinhibitors, antisense oligonucleotides, antisense oligodexoynucleotides,siRNAs, anti-VEGF aptamers, pigment epithelium derived factor andcompounds which have been published in the international patentapplications WO 97/22596, WO 97/30035, WO 97/32856 and WO 98/13354);

(vi) vessel-destroying agents, such as combretastatin A4 and compoundswhich have been published in the international patent applications WO99/02166, WO 00/40529, WO 00/41669, WO 01/92224, WO 02/04434 and WO02/08213;

(vii) antisense therapies, for example those directed to the targetsmentioned above, such as ISIS 2503, an anti-Ras antisense;

(viii) gene therapy approaches, including, for example, approaches forreplacement of abnormal, modified genes, such as abnormal p53 orabnormal BRCA1 or BRCA2, GDEPT approaches (gene-directed enzyme pro-drugtherapy), such as those which use cytosine deaminase, thymidine kinaseor a bacterial nitroreductase enzyme, and approaches which increase thetolerance of a patient to chemotherapy or radiotherapy, such asmulti-drug resistance therapy; and

(ix) immunotherapy approaches, including, for example, ex-vivo andin-vivo approaches for increasing the immunogenicity of tumour cells ofa patient, such as transfection with cytokines, such as interleukin 2,interleukin 4 or granulocyte macrophage colony stimulating factor,approaches for decreasing T-cell anergy, approaches using transfectedimmune cells, such as cytokine-transfected dendritic cells, approachesfor use of cytokine-transfected tumour cells and approaches for use ofanti-idiotypic antibodies

(x) chemotherapeutic agents including for example abarelix, aldesleukin,alemtuzumab, alitretinoin, allopurinol, altretamine, amifostine,anastrozole, arsenic trioxide, asparaginase, BCG live, bevaceizumab,bexarotene, bleomycin, bortezomib, busulfan, calusterone, camptothecin,capecitabine, carboplatin, carmustine, celecoxib, cetuximab,chlorambucil, cinacalcet, cisplatin, cladribine, cyclophosphamide,cytarabine, dacarbazine, dactinomycin, darbepoetin alfa, daunorubicin,denileukin diftitox, dexrazoxane, docetaxel, doxorubicin,dromostanolone, epirubicin, epoetin alfa, estramustine, etoposide,exemestane, filgrastim, floxuridine, fludarabine, fluorouracil,fulvestrant and gemcitabine.

Additional therapeutic agents from table 1 can preferably, but notexclusively, be combined with the compounds of the formula I.

TABLE 1 Alkylating active Cyclophosphamide Lomustine compounds BusulfanProcarbazine Ifosfamide Altretamine Melphalan Estramustine phosphateHexamethylmelamine Mechloroethamine Thiotepa Streptozocin chloroambucilTemozolomide Dacarbazine Semustine Carmustine Platinum active CisplatinCarboplatin compounds Oxaliplatin ZD-0473 (AnorMED) SpiroplatinLobaplatin (Aetema) Carboxyphthalatoplatinum Satraplatin (JohnsonMatthey) Tetraplatin BBR-3464 Ormiplatin (Hoffrnann-La Roche) IproplatinSM-11355 (Sumitomo) AP-5280 (Access) Antimetabolites Azacytidine TomudexGemcitabine Trimetrexate Capecitabine Deoxycoformycin 5-FluorouracilFludarabine Floxuridine Pentostatin 2-Chlorodesoxyadenosine Raltitrexed6-Mercaptopurine Hydroxyurea 6-Thioguanine Decitabine (SuperGen)Cytarabine Clofarabine (Bioenvision) 2-Fluorodesoxycytidine Irofulven(MGI Pharrna) Methotrexate DMDC (Hoffmann-La Roche) IdatrexateEthynylcytidine (Taiho) Topoisomerase Amsacrine Rubitecan (SuperGen)inhibitors Epirubicin Exatecan mesylate (Daiichi) Etoposide Quinamed(ChemGenex) Teniposide or mitoxantrone Gimatecan (Sigma-Tau) Irinotecan(CPT-11) Diflomotecan (Beaufour-Ipsen) 7-ethyl-10-hydroxycamptothecinTAS-103 (Taiho) Topotecan Elsamitrucin (Spectrum) Dexrazoxanet(TopoTarget) J-107088 (Merck & Co) Pixantrone (Novuspharrna) BNP-1350(BioNumerik) Rebeccamycin analogue CKD-602 (Chong Kun Dang) (Exelixis)KW-2170 (Kyowa Hakko) BBR-3576 (Novuspharrna) Antitumour Dactinomycin(Actinomycin D) Amonafide antibiotics Doxorubicin (Adriamycin) AzonafideDeoxyrubicin Anthrapyrazole Valrubicin Oxantrazole Daunorubicin(Daunomycin) Losoxantrone Epirubicin Bleomycin sulfate (Blenoxan)Therarubicin Bleomycinic acid Idarubicin Bleomycin A Rubidazon BleomycinB Plicamycinp Mitomycin C Porfiromycin MEN-10755 (Menarini)Cyanomorpholinodoxorubicin GPX-100 Mitoxantron (Novantron) (GemPharmaceuticals) Antimitotic active Paclitaxel SB 408075 compoundsDocetaxel (GlaxoSmithKline) Colchicine E7010 (Abbott) Vinblastine PG-TXL(Cell Therapeutics) Vincristine IDN 5109 (Bayer) Vinorelbine A 105972(Abbott) Vindesine A 204197 (Abbott) Dolastatin 10 (NCl) LU 223651(BASF) Rhizoxin (Fujisawa) D 24851 (ASTA Medica) Mivobulin(Warner-Lambert) ER-86526 (Eisai) Cemadotin (BASF) Combretastatin A4(BMS) RPR 109881A (Aventis) Isohomohalichondrin-B TXD 258 (Aventis)(PharmaMar) Epothilone B (Novartis) ZD 6126 (AstraZeneca) T 900607(Tularik) PEG-Paclitaxel (Enzon) T 138067 (Tularik) AZ10992 (Asahi)Cryptophycin 52 (Eli Lilly) !DN-5109 (Indena) Vinflunine (Fabre) AVLB(Prescient Auristatin PE (Teikoku NeuroPharma) Hormone) Azaepothilon B(BMS) BMS 247550 (BMS) BNP- 7787 (BioNumerik) BMS 184476 (BMS)CA-4-prodrug (OXiGENE) BMS 188797 (BMS) Dolastatin-10 (NrH) Taxoprexin(Protarga) CA-4 (OXiGENE) Aromatase Aminoglutethimide Exemestaninhibitors Letrozole Atamestan (BioMedicines) Anastrazole YM-511(Yamanouchi) Formestan Thymidylate Pemetrexed (Eli Lilly) Nolatrexed(Eximias) Synthase ZD-9331 (BTG) CoFactor ™ (BioKeys) inhibitors DNAantagonists Trabectedin (PharmaMar) Mafosfamide (Baxter Glufosfamide(Baxter International) International) Apaziquone (Spectrum Albumin + 32PPharmaceuticals) (isotope solutions) O6-benzylguanine (Paligent)Thymectacin (NewBiotics) Edotreotid (Novartis) Farnesyl transferaseArglabin (NuOncology Labs) Tipifarnib inhibitors Lonafarnib(Schering-Plough) (Johnson & Johnson) BAY-43-9006 (Bayer) Perillylalcohol (DOR BioPharma) Pump inhibitors CBT-1 (CBA Pharma) Zosuquidartrihydrochloride Tariquidar (Xenova) (Eli Lilly) MS-209 (Schering AG)Biricodar dicitrate (Vertex) Histone acetyl trans- Tacedinaline (Pfizer)Pivaloyloxymethyl butyrate ferase inhibitors SAHA (Aton Pharma) (Titan)MS-275 (Schering AG) Depsipeptide (Fujisawa) Metalloproteinase Neovastat(Aeterna CMT -3 (CollaGenex) inhibitors Laboratories) BMS-275291(Celltech) Ribonucleoside Marimastat (British Biotech) Tezacitabine(Aventis) reductase Gallium maltolate (Titan) Didox (Molecules forHealth) inhibitors Triapin (Vion) TNF-alpha Virulizin (LorusTherapeutics) Revimid (Celgene) agonists/ CDC-394 (Celgene) antagonistsEndothelin-A Atrasentan (Abbot) YM-598 (Yamanouchi) receptor antagonistsZD-4054 (AstraZeneca) Retinoic acid Fenretinide Alitretinoin (Ligand)receptor agonists (Johnson & Johnson) LGD-1550 (ligand) ImmunomodulatorsInterferon Dexosome therapy (Anosys) Oncophage (Antigenics) Pentrix(Australian Cancer GMK (Progenics) Technology) Adenocarcinoma vaccineJSF-154 (Tragen) (Biomira) Cancer vaccine (Intercell) CTP-37 (AVIBioPharma) Norelin (Biostar) JRX-2 (Immuno-Rx) BLP-25 (Biomira) PEP-005(Peplin Biotech) MGV (Progenics) Synchrovax vaccines !3-Alethin(Dovetail) (CTL Immuno) CLL-Thera (Vasogen) Melanoma vaccines (CTLImmuno) p21-RAS vaccine (GemVax) Hormonal and Oestrogens Prednisoneantihormonal active Conjugated oestrogens Methylprednisolone compoundsEthynyloestradiol Prednisolone Chlorotrianisene AminoglutethimideIdenestrol Leuprolide Hydroxyprogesterone Goserelin caproate LeuporelinMedroxyprogesterone Bicalutamide Testosterone Flutamide Testosteronepropionate Octreotide Fluoxymesterone Nilutamide MethyltestosteroneMitotan Diethylstilbestrol P-04 (Novogen) Megestrol 2-MethoxyoestradiolTamoxifen (En_-treMed) Toremofin Arzoxifen (Eli Lilly) DexamethasonePhotodynamic Talaporfin (Light Sciences) Pd bacteriopheophorbide activecompounds Theralux (Theratechnologies) (Yeda) Motexafin-GadoliniumLutetium texaphyrin (Pharmacyclics) (Pharmacyclics) Hypericin Tyrosinekinase Imatinib (Novartis) Kahalide F (PharmaMar) inhibitorsLeflunomide(Sugen/Pharmacia) CEP- 701 (Cephalon) ZDI839 (AstraZeneca)CEP-751 (Cephalon) Erlotinib (Oncogene Science) MLN518 (Millenium)Canertjnib (Pfizer) PKC412 (Novartis) Squalamine (Genaera) Phenoxodiol OSU5416 (Pharmacia) Trastuzumab (Genentech) SU6668 (Pharmacia) C225(ImClone) ZD4190 (AstraZeneca) rhu-Mab (Genentech) ZD6474 (AstraZeneca)MDX-H210 (Medarex) Vatalanib (Novartis) 2C4 (Genentech) PKI166(Novartis) MDX-447 (Medarex) GW2016 (GlaxoSmithKline) ABX-EGF (Abgenix)EKB-509 (Wyeth) IMC-1C11 (ImClone) EKB-569 (Wyeth) Various other activeSR-27897 (CCK-A inhibitor, BCX-1777 (PNP inhibitor, compoundsSanofi-Synthelabo) BioCryst) Tocladesine Ranpirnase (ribonuclease(cyclic AMP agonist, Ribapharm) stimulant, Alfacell) AlvocidibGalarubicin (RNA synthesis (CDK inhibitor, Aventis) inhibitor, Dong-A)CV-247 Tirapazamine (reducing (COX-2 inhibitor, Ivy Medical) agent, SRIInternational) P54 (COX-2 inhibitor, N-Acetylcysteine Phytopharm)(reducing agent, CapCell ™ (CYP450 Zambon) stimulant, Bavarian Nordic)R-Flurbiprofen (NF-kappaB GCS-IOO (gal3 antagonist, inhibitor, Encore)GlycoGenesys) 3CPA (NF-kappaB inhibitor, G17DT immunogen (gastrin ActiveBiotech) inhibitor, Aphton) Seocalcitol (vitamin D Efaproxiral(oxygenator, receptor agonist, Leo) Allos Therapeutics) 131-I-TM-601(DNA PI-88 (heparanase inhibitor, antagonist, TransMolecular) Progen)Eflornithin (ODC inhibitor, Tesmilifen (histamine ILEX Oncology)antagonist, YM BioSciences) Minodronic acid (osteoclast Histamine(histamine H2 inhibitor, receptor agonist, Maxim) Yamanouchi) Tiazofurin(IMPDH inhibitor, Indisulam (p53 stimulant, Ribapharm) Eisai)Cilengitide (integrin antagonist, Aplidin (PPT inhibitor, Merck KGaA)PharmaMar) SR-31747 (IL-1 antagonist, Rituximab (CD20 antibody,Sanofi-Synthelabo) Genentech) CCI-779 (mTOR kinase Gemtuzumab (CD33inhibitor, Wyeth) antibody, Wyeth Ayerst) Exisulind (PDE-V inhibitor,PG2 (haematopoiesis Cell Pathways) promoter, Pharmagenesis) CP-461(PDE-V inhibitor, Cell Immunol ™ (triclosan Pathways) mouthwash, Endo)AG-2037 (GART inhibitor, Triacetyluridine (uridine Pfizer) prodrug,Wellstat) WX-UK1 (plasminogen SN-4071 (sarcoma agent, activatorinhibitor, Wilex) Signature BioScience) PBI-1402 (PMN stimulant,TransMID-107 ™ ProMetic LifeSciences) (immunotoxin, KS Biomedix)Bortezomib (proteasome PCK-3145 (apoptosis pro- inhibitor, Millennium)moter, Procyon) SRL-172 (T-cell stimulant, Doranidazole (apoptosis pro-SR Pharma) moter, Pola) TLK-286 (glutathione-S CHS-828 (cytotoxic agent,transferase inhibitor, Telik) Leo) PT-100 (growth factor trans-Retinoicacid agonist, Point Therapeutics) (differentiator, NIH) Midostaurin (PKCinhibitor, MX6 (apoptosis promoter, Novartis) MAXIA) Bryostatin-1 (PKCstimulant, Apomine (apoptosis GPC Biotech) promoter, ILEX Oncology)CDA-II (apoptosis promoter, Urocidin (apoptosis promoter, Everlife)Bioniche) SDX-101 (apoptosis promoter, Ro-31-7453 (apoptosis pro-Salmedix) moter, La Roche) Ceflatonin (apoptosis pro- Brostallicin(apoptosis moter, ChemGenex) promoter, Pharmacia)

Even without further embodiments, it is assumed that a person skilled inthe art will be able to use the above description in the broadest scope.The preferred embodiments should therefore merely be regarded asdescriptive disclosure which is absolutely not limiting in any way.

The following examples are thus intended to explain the inventionwithout limiting it. Unless indicated otherwise, percent data denotepercent by weight. All temperatures are indicated in degrees Celsius.“Conventional work-up”: water is added if necessary, the pH is adjusted,if necessary, to values between 2 and 10, depending on the constitutionof the end product, the mixture is extracted with ethyl acetate ordichloromethane, the phases are separated, the organic phase is driedover sodium sulfate, filtered and evaporated, and the product ispurified by chromatography on silica gel and/or by crystallisation.

List of Abbreviations

-   AUC Area under the plasma drug concentration-time curve-   C_(max) Maximum plasma concentration-   CL Clearance-   CV Coefficient of variation-   CYP Cytochrome P450-   DMSO Dimethyl sulfoxide-   % F Bioavailability-   f_(a) Fraction absorbed-   iv Intravenous-   LC-MS/MS Liquid chromatography tandem mass spectrometry-   LLOQ Lower limit of quantification-   NC Not calculated-   NT Not tested-   PEG Polyethylene glycol-   Pgp Permeability glycoprotein-   PK Pharmacokinetic(s)-   po Per os (oral)-   t_(1/2) Half-life-   t_(max) Time at which maximum plasma concentration of drug is    reached-   UPLC Ultra performance liquid chromatography-   V_(ss) Volume of distribution (at steady state)-   v/v Volume to volume

Example 1: Examples of Compounds of the Present Invention

The invention especially relates to the compounds of Table 2 andphysiologically acceptable salts, derivatives, solvates, prodrugs,stereoisomers and atropisomers thereof, including mixtures thereof inall ratios.

TABLE 2 examples of compounds of the present invention No. StructureIUPAC-Name 1

2-(4-amino-4-methylpiperidin-1-yl)- 5-(2,3-dichloro-phenyl)-pyrimidine-4-carboxamide 2

6-Amino-2-(4-amino-4-methyl- piperidin-1-yl)-5-(3-chloro-phenyl)-pyrimidine-4-carboxylic acid amide 3

6-Amino-2-(4-amino-4-methyl- piperidin-1-yl)-5-(2,3-dichloro-phenyl)-pyrimidine-4-carboxylic acid amide 4

6-Amino-2-(4-amino-4-methyl- piperidin-1-yl)-5-(3-fluoro-phenyl)-pyrimidine-4-carboxylic acid amide 5

6-amino-2-[(3S,4S)-4-amino-3- methyl-2-oxa-8-azaspiro-[4.5]decan-8-yl]-5-(2,3- dichlorophenyl)pyrimidine-4- carboxamide 6

6-amino-2-{9-amino-3- azabicyclo[3.3.1]nonan-3-yl}-5-(2,3-dichlorophenyl)-pyrimidine-4- carboxamide 7

6-amino-2-[(1R)-1-amino-8- azaspiro[4.5]decan-8-yl]-5-(2,3-dichlorophenyl)-pyrimidine-4- carboxamide 8

6-amino-2-[(1R)-1-amino-3,3- difluoro-8-azaspiro[4.5]-decan-8-yl]-5-(2,3-dichloro-phenyl)- pyrimidine-4-carboxamide 9

6-Amino-2-(4-amino-4-methyl- piperidin-1-yl)-5-(2,3-dichloro-phenyl)-pyrimidine-4-carboxylic acid methylamide 10

6-amino-2-[6-amino-7-hydroxy-1- (propan-2-yl)-2-azaspiro[3.4]octan-2-yl]-5-(2,3-dichlorophenyl)- pyrimidine-4-carboxamide 11

6-amino-2-[8-(aminomethyl)-6- azaspiro[3.4]octan-6-yl]-5-(2,3-dichlorophenyl)-pyrimidine-4- carboxamide 12

6-amino-2-[3-(aminomethyl)-8- azabicyclo[3.2.1]octan-8-yl]-5-(2,3-dichlorophenyl)-pyrimidine-4- carboxamide 13

6-amino-5-(2,3-dichlorophenyl)-2- [(1R,7S,11s)-11-amino-1,7-dimethyl-9-azabicyclo[5.3.1]- undecan-9-yl]pyrimidine-4- carboxamide 14

6-amino-5-(2,3-dichlorophenyl)-2- [(1R,7S,11r)-11-amino-1,7-dimethyl-9-azabicyclo[5.3.1]- undecan-9-yl]pyrimidine-4- carboxamide 15

2-(4-Amino-4-methyl-piperidin-1- yl)-5-(2,3-dichloro-phenyl)-6-hydroxy-pyrimidine-4-carboxylic acid amide 16

2-(4-Amino-4-methyl-piperidin-1- yl)-6-chloro-5-(2,3-dichloro-phenyl)-pyrimidine-4-carboxylic acid amide 17

6-Amino-2-(4-amino-4-methyl- piperidin-1-yl)-5-(2,3-dichloro-phenyl)-pyrimidine-4-carboxylic- acid-(2-hydroxy-ethyl)-amide 18

2-(4-Amino-4-methyl-piperidin-1- yl)-5-(2,3-dichlorophenyl)-6-methyl-pyrimidine-4-carboxylic acid amide 19

2-(4-Amino-4-methyl-piperidin-1- yl)-6-chloro-5-(3-fluoro-phenyl)-pyrimidine-4-carboxylic acid amide 20

6-Amino-2-(4-amino-4-methyl- piperidin-1-yl)-5-(2,3-dichloro-phenyl)-pyrimidine-4-carboxylic acid hydroxyamide 21

6-Amino-2-(4-amino-4-methyl- piperidin-1-yl)-5-(2,3-dichloro-phenyl)-pyrimidine-4-carboxylic acid hydrazide 22

2-(4-Amino-4-methyl-piperidin-1- yl)-6-fluoro-5-(3-fluoro-phenyl)-pyrimidine-4-carboxylic acid amide 23

6-amino-2-[4-(aminomethyl)-8-oxa- 2-azaspiro[4.5]decan-2-yl]-5-(2,3-dichlorophenyl)-pyrimidine-4- carboxamide 24

2-[3a-(aminomethyl)-octahydro-1H- isoindol-2-yl]-6-amino-5-(2,3-dichlorophenyl)-pyrimidine-4- carboxamide 25

2-(4-Amino-4-methyl-piperidin-1- yl)-5-(3-fluoro-phenyl)-6-hydroxy-pyrimidine-4-carboxylic acid amide 26

(4M)-6-amino-2-(4-amino-4- methylpiperidin-1-yl)-5-(2,3-dichlorophenyl)pyrimidine-4- carboxamide 27

(4P)-6-amino-2-(4-amino-4- methylpiperidin-1-yl)-5-(2,3-dichlorophenyl)pyrimidine-4- carboxamide 28

2-(3-Amino-cyclohexyl-amino)-5- (2,3-dichloro-phenyl)-6-methyl-pyrimidine-4-carboxylic acid amide 29

6-amino-2-[4-amino-4- (hydroxymethyl)piperidin-1-yl]-5-(2,3-dichlorophenyl)-pyrimidine-4- carboxamide 30

(4M)-2-(4-amino-4-methyl- piperidin-1-yl)-5-(2,3-dichloro-phenyl)-6-methylpyrimidine-4- carboxamide 31

(4P)-2-(4-amino-4-methyl-piperidin- 1-yl)-5-(2,3-dichloro-phenyl)-6-methylpyrimidine-4-carboxamide 32

2-[(4-Amino-cyclohexyl)-methyl- amino]-5-(2,3-dichlorophenyl)-6-methyl-pyrimidine-4-carboxylic acid amide 33

2-(7-Amino-3-oxa-9-aza- bicyclo[3.3.1]non-9-yl)-5-(2,3-dichlorophenyl)-6-methyl- pyrimidine-4-carboxylic acid amide 34

6-amino-2-[8-(aminomethyl)-2-oxa- 6-azaspiro[3.4]octan-6-yl]-5-(2,3-dichloro-phenyl)pyrimidine-4- carboxamide 35

2-((R)-6-Amino-2-aza- spiro[4.4]non-2-yl)-5-(2,3-dichloro-phenyl)-6-methyl-pyrimidine-4- carboxylic acid amide 36

2-(3-Aminomethyl- cyclopentylamino)-5-(2,3-dichloro-phenyl)-6-methyl-pyrimidine-4- carboxylic acid amide 37

2-((S)-6-Amino-2-aza- spiro[4.4]non-2-yl)-5-(2,3-dichloro-phenyl)-6-methyl-pyrimidine-4- carboxylic acid amide 38

6-amino-2-{4-amino-1-oxa-9- azaspiro[5.5]undecan-9-yl}-5-(2,3-dichlorophenyl)pyrimidine-4- carboxamide 39

6-amino-2-[4-(3-aminooxan-2- yl)piperidin-1-yl]-5-(2,3-dichlorophenyl)pyrimidine-4- carboxamide 40

6-amino-2-[3-(aminomethyl)-2-oxa- 8-azaspiro[4.5]decan-8-yl]-5-(2,3-dichlorophenyl)pyrimidine-4- carboxamide 41

6-amino-2-[4-(aminomethyl)-4- methylpiperidin-1-yl]-5-(2,3-dichlorophenyl)pyrimidine-4- carboxamide 42

2-(4-Amino-hexahydro- cyclopenta[c]pyrrol-2-yl)-5-(2,3-dichloro-phenyl)-6-methyl- pyrimidine-4-carboxylic acid amide 43

2-(2-Aminomethyl- cyclopentylamino)-5-(2,3-dichloro-phenyl)-6-methyl-pyrimidine-4- carboxylic acid amide 44

2-(3-Aminomethyl-3-fluoro-azetidin- 1-yl)-5-(2,3-dichloro-phenyl)-6-methyl-pyrimidine-4-carboxylic acid amide 45

2-(4-Amino-4-methyl-azepan-1-yl)- 5-(2,3-dichloro-phenyl)-6-methyl-pyrimidine-4-carboxylic acid amide 46

2-(2-Aminomethyl-azetidin-1-yl)-5- (2,3-dichloro-phenyl)-6-methyl-pyrimidine-4-carboxylic acid amide 47

(4P)-2-[(3R)-3- (aminomethyl)morpholin-4-yl]-5- (2,3-dichlorophenyl)-6-methylpyrimidine-4-carboxamide 48

(4P)-2-[(3S)-3- (aminomethyl)morpholin-4-yl]-5- (2,3-dichlorophenyl)-6-methylpyrimidine-4-carboxamide 49

6-amino-2-(4-aminoazepan-1-yl)-5- (2,3-dichlorophenyl)-pyrimidine-4-carboxamide 50

6-amino-2-(4-amino-octahydro-1H- isoindol-2-yl)-5-(2,3-dichlorophenyl)pyrimidine-4- carboxamide 51

6-amino-2-[(3R,4R)-3- (aminomethyl)-4-phenylpyrrolidin- 1-yl]-5-(2,3-dichlorophenyl)pyrimidine-4- carboxamide 52

6-amino-2-({4- azaspiro[bicyclo[2.2.2]octane-2,2′-oxan]-4′-yl}amino)-5-(2,3- dichlorophenyl)pyrimidine-4- carboxamide 53

6-amino-2-(4-amino-4- propylpiperidin-1-yl)-5-(2,3-dichloro-phenyl)pyrimidine-4- carboxamide 54

6-amino-2-[3-(aminomethyl)-3- hydroxyazetidin-1-yl]-5-(2,3-dichlorophenyl)-pyrimidine-4- carboxamide 55

6-amino-2-[3-(aminomethyl)-3- methylazetidin-1-yl]-5-(2,3-dichlorophenyl)pyrimidine-4- carboxamide 56

5-(2,3-Dichloro-phenyl)-6-methyl-2- (5-methyl-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-pyrimidine-4- carboxylic acid amide 57

2-(3-Amino-3-hydroxymethyl- azetidin-1-yl)-5-(2,3-dichloro-phenyl)-6-methyl-pyrimidine-4- carboxylic acid amide 58

2-(1-Amino-5-aza-spiro[2.4]hept-5- yl)-5-(2,3-dichloro-phenyl)-6-methyl-pyrimidine-4-carboxylic acid amide 60

2-(4-Amino-4-methyl-piperidin-1- yl)-5-(1H-benzoimidazol-4-yl)-pyrimidine-4-carboxylic acid amide 61

2-(4-Amino-4-methyl-piperidin-1- yl)-5-benzo[1,2,5]-oxadiazol-4-yl-pyrimidine-4-carboxylic acid amide 62

6-Amino-2-(4-amino-4-methyl- piperidin-1-yl)-5-(7-chloro-1H-indazol-6-yl)-pyrimidine-4- carboxylic acid amide 63

5-(2,3-Dichloro-phenyl)-6-methyl-2- (5-methyl-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-pyrimidine-4- carboxylic acid amide 64

(5M)-6-amino-5-(2,3- dichlorophenyl)-2-{[(3S,4R)-3-fluoropiperidin-4-yl]amino}- pyrimidine-4-carboxamide 65

6-amino-2-{[(1R,2S)-2- aminocyclohexyl]amino}-5-(2,3-dichlorophenyl)-pyrimidine-4- carboxamide 66

(5P)-6-amino-2-[(3S,4S)-4-amino- 3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl]-5-(2,3- dichlorophenyl)-pyrimidine-4-carboxamide 67

(5M)-6-amino-2-[(3S,4S)-4-amino- 3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl]-5-(2,3- dichlorophenyl)-pyrimidine-4-carboxamide 68

2-(3,9-Diaza-bicyclo[4.2.1]-non-3- yl)-5-(2,3-dichloro-phenyl)-6-methyl-pyrimidine-4-carboxylic acid amide 69

6-amino-2-(3-aminoazetidin-1-yl)-5- (2,3-dichlorophenyl)-pyrimidine-4-carboxamide 70

6-amino-2-[(1R,5S,6R)-6- (aminomethyl)-3-azabicyclo-[3.1.0]hexan-3-yl]-5-(2,3- dichlorophenyl)pyrimidine-4- carboxamide 71

6-amino-2-[2-(aminomethyl)- azetidin-1-yl]-5-(2,3-dichlorophenyl)pyrimidine-4- carboxamide 72

2-((3aR,4R,6aS)-4-Amino- hexahydro-cyclopenta-[c]pyrrol-2-yl)-5-(2,3-dichloro-phenyl)-6- methyl-pyrimidine-4-carboxylic acid amide73

2-((3aS,6aS)-4-Amino-hexahydro- cyclopenta-[c]pyrrol-2-yl)-5-(2,3-dichloro-phenyl)-6-methyl- pyrimidine-4-carboxylic acid amide 74

2-((3aS,4S,6aR)-4-Amino- hexahydro-cyclopenta-[c]pyrrol-2-yl)-5-(2,3-dichloro-phenyl)-6- methyl-pyrimidine-4-carboxylic acid amide75

2-((3aS,4R,6aR)-4-Amino- hexahydro-cyclopenta[c]pyrrol-2-yl)-5-(2,3-dichloro-phenyl)-6- methyl-pyrimidine-4-carboxylic acid amide76

2-((3aR,6aR)-4-Amino-hexahydro- cyclopenta-[c]pyrrol-2-yl)-5-(2,3-dichloro-phenyl)-6-methyl- pyrimidine-4-carboxylic acid amide 77

2-((3aR,4S,6aS)-4-Amino- hexahydro-cyclopenta-[c]pyrrol-2-yl)-5-(2,3-dichloro-phenyl)-6- methyl-pyrimidine-4-carboxylic acid amide78

(4M)-2-(4-amino-4-methylpiperidin- 1-yl)-6-chloro-5-(2,3-dichlorophenyl)-pyrimidine-4- carboxamide 79

(4P)-2-(4-amino-4-methylpiperidin- 1-yl)-6-chloro-5-(2,3-dichlorophenyl)-pyrimidine-4- carboxamide 80

2-((3R,4S)-3-Amino-4-hydroxy- pyrrolidin-1-yl)-5-(2,3-dichloro-phenyl)-6-methyl-pyrimidine-4- carboxylic acid amide 81

2-(4-Amino-4-methyl-piperidin-1- yl)-5-(2,3-dichloro-pyridin-4-yl)-6-methyl-pyrimidine-4-carboxylic acid amide 82

2-(4-Amino-4-methyl-piperidin-1- yl)-5-(2-chloro-4-fluoro-phenyl)-6-methyl-pyrimidine-4-carboxylic acid amide 83

2-(4-Amino-4-methyl-piperidin-1- yl)-5-(4-chloro-pyridin-3-yl)-6-methyl-pyrimidine-4-carboxylic acid amide 84

2-((3S,4S)-3-Amino-4-hydroxy- pyrrolidin-1-yl)-5-(2,3-dichloro-phenyl)-6-methyl-pyrimidine-4- carboxylic acid amide 85

2-[(3S,4S)-4-amino-3-methyl-2- oxa-8-azaspiro[4.5]decan-8-yl]-5-(2,3-dichlorophenyl)-6- methylpyrimidine-4-carboxamide 86

2-(4-Amino-4-methyl-piperidin-1- yl)-6-methyl-5-pyridin-4-yl-pyrimidine-4-carboxylic acid amide 87

(4M)-2-{[(1S,3R)-3- aminocyclohexyl]amino}-5-(2,3- dichlorophenyl)-6-methylpyrimidine-4-carboxamide 88

(4M)-2-{[(1R,3S)-3- aminocyclohexyl]amino}-5-(2,3- dichlorophenyl)-6-methylpyrimidine-4-carboxamide 89

(4P)-2-{[(1R,3S)-3- aminocyclohexyl]amino}-5-(2,3- dichlorophenyl)-6-methylpyrimidine-4-carboxamide 90

(4P)-2-{[(1S,3R)-3- aminocyclohexyl]amino}-5-(2,3- dichlorophenyl)-6-methylpyrimidine-4-carboxamide 91

6-Amino-2-(4-amino-4-methyl- azepan-1-yl)-5-(2,3-dichloro-phenyl)-pyrimidine-4-carboxylic acid amide 92

2-(4-Amino-4-methyl-piperidin-1- yl)-5-(1H-indol-3-yl)-6-methyl-pyrimidine-4-carboxylic acid amide 93

2-(4-Amino-cyclohexyl-amino)-5- (2,3-dichloro-phenyl)-6-methyl-pyrimidine-4-carboxylic acid amide 94

(5P)-2-[(3S,4S)-4-amino-3-methyl- 2-oxa-8-azaspiro[4.5]-decan-8-yl]-5-(2,3-dichloro-phenyl)-6- methylpyrimidine-4-carboxamide 95

(5M)-2-[(3S,4S)-4-amino-3-methyl- 2-oxa-8-azaspiro[4.5]-decan-8-yl]-5-(2,3-dichloro-phenyl)-6- methylpyrimidine-4-carboxamide 96

(5M)-2-[(1R)-1-amino-3,3-difluoro- 8-azaspiro[4.5]-decan-8-yl]-5-(2,3-dichloro-phenyl)-6- methylpyrimidine-4-carboxamide 97

(5P)-2-[(1R)-1-amino-3,3-difluoro- 8-azaspiro[4.5]-decan-8-yl]-5-(2,3-dichlorophenyl)-6- methylpyrimidine-4-carboxamide 98

(5P)-2-[(3aR,6aS)-3a- (aminomethyl)-octahydro-cyclopenta[c]pyrrol-2-yl]-6-amino-5- (2,3-dichlorophenyl)-pyrimidine-4-carboxamide 99

(5M)-2-[(3aR,6aS)-3a- (aminomethyl)-octahydro-cyclopenta[c]pyrrol-2-yl]-6-amino-5- (2,3-dichlorophenyl)-pyrimidine-4-carboxamide 100

(5P)-2-[(3aR,7aS)-3a- (aminomethyl)-octahydro-1H-isoindol-2-yl]-6-amino-5-(2,3- dichlorophenyl)pyrimidine-4- carboxamide101

(5P)-2-[(3aS,7aR)-3a- (aminomethyl)-octahydro-1H-isoindol-2-yl]-6-amino-5-(2,3- dichlorophenyl)pyrimidine-4- carboxamide102

(5M)-2-[(3aR,7aS)-3a- (aminomethyl)-octahydro-1H-isoindol-2-yl]-6-amino-5-(2,3- dichlorophenyl)pyrimidine-4- carboxamide103

(5M)-2-[(3aS,7aR)-3a- (aminomethyl)-octahydro-1H-isoindol-2-yl]-6-amino-5-(2,3- dichlorophenyl)pyrimidine-4- carboxamide104

(5P)-2-[(3aS,6aR)-3a- (aminomethyl)-octahydro-cyclopenta[c]pyrrol-2-yl]-6-amino-5- (2,3-dichlorophenyl)-pyrimidine-4-carboxamide 105

(5M)-2-[(3aS,6aR)-3a- (aminomethyl)-octahydro-cyclopenta[c]pyrrol-2-yl]-6-amino-5- (2,3-dichlorophenyl)-pyrimidine-4-carboxamide 106

(5P)-6-amino-2-[4-amino-4- (difluoromethyl)piperidin-1-yl]-5-(2,3-dichlorophenyl)-pyrimidine-4- carboxamide 107

(5M)-6-amino-2-[4-amino-4- (difluoromethyl)piperidin-1-yl]-5-(2,3-dichlorophenyl)-pyrimidine-4- carboxamide 108

(5P)-6-amino-2-[(4S)-4-amino-4- methylazepan-1-yl]-5-(2,3-dichlorophenyl)-pyrimidine-4- carboxamide 109

(5P)-6-amino-2-[(4R)-4-amino-4- methylazepan-1-yl]-5-(2,3-dichlorophenyl)-pyrimidine-4- carboxamide 110

(5M)-6-amino-2-[(4S)-4-amino-4- methylazepan-1-yl]-5-(2,3-dichlorophenyl)-pyrimidine-4- carboxamide 111

2-(4-Amino-4-methyl-piperidin-1- yl)-5-(2-chloro-3-trifluoromethyl-phenyl)-6-methyl-pyrimidine-4- carboxylic acid amide 112

6-Amino-2-[(4-amino-cyclohexyl)- methyl-amino]-5-(2,3-dichloro-phenyl)-pyrimidine-4-carboxylic acid amide 113

(5P)-2-[(1R)-1-amino-8- azaspiro[4.5]decan-8-yl]-5-(2,3-dichlorophenyl)-6- methylpyrimidine-4-carboxamide 114

(5M)-2-[(1R)-1-amino-8- azaspiro[4.5]decan-8-yl]-5-(2,3-dichlorophenyl)-6- methylpyrimidine-4-carboxamide 115

(4M)-2-(4-amino-4-methylpiperidin-1- yl)-5-(2-chloro-4-fluoro-3-methoxyphenyl)-6-methylpyrimidine-4- carboxamide 116

(4P)-2-(4-amino-4-methylpiperidin-1- yl)-5-(2-chloro-4-fluoro-3-methoxyphenyl)-6-methylpyrimidine-4- carboxamide 117

(5P)-6-amino-2-[(1S)-1-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl]-5-(2,3-dichlorophenyl)pyrimidine-4- carboxamide 118

(5M)-6-amino-2-[(1S)-1-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl]-5-(2,3-dichlorophenyl)pyrimidine-4- carboxamide 119

(5M)-2-[(1S)-1-amino-1,3- dihydrospiro[indene-2,4′-piperidin]-1′-yl]-5-(2,3-dichlorophenyl)-6- methylpyrimidine-4-carboxamide 120

(5P)-2-[(1S)-1-amino-1,3- dihydrospiro[indene-2,4′-piperidin]-1′-yl]-5-(2,3-dichlorophenyl)-6- methylpyrimidine-4-carboxamide 121

6-amino-2-[(4S)-4-amino-4,6- dihydrospiro[cyclopenta[d][1,3]thiazole-5,4′-piperidin]-1′-yl]-5-(2,3- dichlorophenyl)pyrimidine-4- carboxamide122

2-[(3R)-3-amino-3H-spiro[1- benzofuran-2,4′-piperidin]-1′-yl]-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4- carboxamide 123

6-amino-2-[(3R)-3-amino-3H-spiro[1-benzofuran-2,4′-piperidin]-1′-yl]-5-(2,3- dichlorophenyl)pyrimidine-4-carboxamide 124

(4M)-2-[(3R)-3-amino-3H- spiro[furo[2,3-b]pyridine-2,4′-piperidin]-1′-yl]-5-(2,3-dichlorophenyl)-6- methylpyrimidine-4-carboxamide 125

(4M)-2-[(3S)-3-amino-3H- spiro[furo[2,3-b]pyridine-2,4′-piperidin]-1′-yl]-5-(2,3-dichlorophenyl)-6- methylpyrimidine-4-carboxamide 126

(4P)-2-[(3R)-3-amino-3H- spiro[furo[2,3-b]pyridine-2,4′-piperidin]-1′-yl]-5-(2,3-dichlorophenyl)-6- methylpyrimidine-4-carboxamide 127

(4P)-2-[(3S)-3-amino-3H-spiro[furo[2,3-b]pyridine-2,4′-piperidin]-1′-yl]-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4- carboxamide 128

(4P)-6-amino-2-[(3R)-3-amino-3H-spiro[furo[2,3-b]pyridine-2,4′-piperidin]-1′-yl]-5-(2,3-dichlorophenyl)pyrimidine- 4-carboxamide 129

(4P)-6-amino-2-[(3S)-3-amino-3H-spiro[furo[2,3-b]pyridine-2,4′-piperidin]-1′-yl]-5-(2,3-dichlorophenyl)pyrimidine- 4-carboxamide 130

(4M)-6-amino-2-[(3R)-3-amino-3H-spiro[furo[2,3-b]pyridine-2,4′-piperidin]-1′-yl]-5-(2,3-dichlorophenyl)pyrimidine- 4-carboxamide 131

(4M)-6-amino-2-[(3S)-3-amino-3H-spiro[furo[2,3-b]pyridine-2,4′-piperidin]-1′-yl]-5-(2,3-dichlorophenyl)pyrimidine- 4-carboxamide

Example 2: Preparation of the Compounds of the Present Invention andAnalytical Methods

The abbreviations below have the following meanings:

-   Boc ter-butoxycarbonyl-   CBZ benzyloxycarbonyl-   DNP 2,4-dinitrophenyl-   FMOC 9-fluorenylmethoxycarbonyl-   imi-DNP 2,4-dinitrophenyl in the 1-position of the imidazole ring-   OMe methyl ester-   POA phenoxyacetyl-   DCCldicyclohexylcarbodiimide-   HOBt1-hydroxybenzotriazole

In general, the compounds according to Formula (I) and related formulaeof this invention can be prepared from readily available startingmaterials. If such starting materials are not commercially available,they may be prepared by standard synthetic techniques. In general, thesynthesis pathways for any individual compound of Formula(I) and relatedformulae will depend on the specific substituents of each molecule, suchfactors being appreciated by those of ordinary skilled in the art. Thefollowing general methods and procedures described hereinafter in theexamples may be employed to prepare compounds of Formula (I) and relatedformulae. Those methods are illustrative and are not meant to limit thepossible methods one skilled in the art may use to prepare compoundsdisclosed herein. Reaction conditions depicted in the following schemes,such as temperatures, solvents, or co-reagents, are given as examplesonly and are not restrictive. It will be appreciated that where typicalor preferred experimental conditions (i.e. reaction temperatures, time,moles of reagents, solvents etc.) are given, other experimentalconditions can also be used unless otherwise stated. Optimum reactionconditions may vary with the particular reactants or solvents used, butsuch conditions can be determined by the person skilled in the art,using routine optimisation procedures. For all the protection anddeprotection methods, see Philip J. Kocienski, in “Protecting Groups”,Georg Thieme Verlag Stuttgart, New York, 1994 and, Theodora W. Greeneand Peter G. M. Wuts in “Protective Groups inOrganic Synthesis”, WileyInterscience, 3rd Edition 1999.

Depending on the nature of R1, R2, R3, R4, R5, X and Y differentsynthetic strategies may be selected for the synthesis of compounds ofFormula (I). In the process illustrated in the following schemes, R1,R2, R3, R4, R5, X and Y are as above defined in the description unlessotherwise mentioned.

According to one process, pyrimidine derivatives according to thegeneral formula 4 wherein R2 and R3 are as above described, R20 and R21are H, substituted alkyl, heteroalkyl or can combine to form amonocyclic or polycyclic alkyl or heteroalkyl which may or may not besubstituted and R8 is COYR4R5 wherein Y, R4 and R5 are as abovedescribed or CN can be prepared following reaction scheme described inscheme 1.

Pyrimidine 1 wherein R3 and R8 are as above described and LG1 is aleaving group such as a halogen or OMs, OTs, OTf undergoes asubstitution reaction with an amine NHR20R21 wherein R20 and R21 are asabove described by heating in a solvent such as, but not limited toMeOH, EtOH, DMF, DMSO in the presence or absence of a base such as TEA,DIEA, Cs₂CO₃ or K₂CO₃ to give a pyrimidine of general formula 2 whereinR3, R20, R21 and R8 are as above defined. Pyridine 2 is then submittedto halogenation conditions using for example NBS, NCS or NIS to give anintermediate of general formula 3 wherein R3, R20, R21 and R8 are asabove describe and Hal is a halogen atom such as Cl, Br or I. Finally,pyrimidine 3 undergoes a cross coupling reaction to give pyrimidine 4using standard conditions well known to one skilled in the art. In someembodiments, the cross-coupling reaction is a Suzuki reaction, but othercross coupling reactions may be employed. Alternatively, pyrimidinederivatives according to the general formula 4 wherein R2, R3, R20, R21,R8 are as above defined can be prepared following reaction schemedescribed in scheme 2.

In this reaction sequence, thiomethyl compound 5 wherein R3 and R8 areas above defined is first submitted to halogenation and then crosscoupling conditions to give intermediate compound 7 wherein R2, R3, R8are as above defined. Thiomethyl group is then oxidized to SO₂Me usingstandard conditions well known to one skilled in the art such as e.g.mCPBA or H₂O₂ to give intermediate 8 wherein R2, R3 and R8 are as abovedefined. Finally, Intermediate 8 undergoes a substitution reaction withNHR20R21 wherein R20 and R21 are as above defined.

To obtain final compounds of general formula Ia, a last transformationof R8 may be required.

When R8 is COOR19 wherein R19 is H, alkyl, cycloalkyl, final compoundsof general formula I are produced when COOR19 is reacted with an amineHNR4R5 wherein R4 and R5 are as above described using conditions wellknown to one skilled in the art to prepare an amide from an amine and acarboxylic acid or a carboxylic acid derivative with standard couplingagents such as e.g. DIC, EDC, TBTU, DECP, or others as depicted inscheme 3.

When R8 is CN, final compounds of general formula I wherein R2, R3, R4,R20 and R21 are as above defined may be obtained by hydrolysis of acompound of general formula 4b wherein R2, R3, R5 and R7 are as abovedefined to an acid of general formula 9 wherein R2, R3, R5 and R7followed by an amide coupling reaction as depicted in scheme 4.Alternatively, compounds of general formula Ib may be obtained by directhydrolysis of a compound of general formula 4b wherein R2, R3, R5 and R7using condition well known from the one skilled in the art such as e.g.heating in presence of NaOH and H₂O₂ in DMF or DMSO.

For the synthesis of other compounds of general formula I, similarsynthetic schemes should be applied with suitable modifications adaptedto specific substituent of each molecules, such factors beingappreciated by those of ordinary skilled in the art.

According to a further general process, compounds of formula I can beconverted to alternative compounds of formula I, employing suitableinterconversion techniques such as hereinafter described in theExamples.

All NMR experiments were recorded on Bruker Avance III 400 NMRSpectrometer equipped with a Bruker PABBO BB-1H/D Z GRD probe at 400 MHzfor proton NMR or a Bruker DPX-300 MHz. Most deuterated solventscontained typically 0.03% to 0.05% v/v tetramethylsilane, which was usedas the reference signal (set at 0.00 for both ¹H and ¹³C). In caseswhere the deuterated solvents did not contain tetramethylsilane, theresidual non-deuterated solvent peaks were used as a reference signal,as per published guidelines (J. Org. Chem., Vol. 62, No. 21, 1997).Chemical shifts are expressed in parts per million (ppm, 6 units).Coupling constants are in units of hertz (Hz). Splitting patternsdescribe apparent multiplicities and are designated as s (singlet), d(doublet), t (triplet), q (quartet), m (multiplet), qt (quintuplet) orbrs (broad singlet).

The following abbreviations refer to the abbreviations used below:

Ac (acetyl); ACN (acetonitrile); atm (atmosphere); DIEA (Di-isopropylethylamine); ° C. (degrees centigrade); DMF (dimethylformamide); DMSO(dimethylsulfoxide); dppf (1,1′-bis-diphenyl phosphine ferrocene); EtOAc(Ethylacetate); g (gram); h (hour); HATU(N-[(Dimethylamino)(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yloxy)methylene]-N-methylmethanaminiumhexafluorophosphate); HOBt (Hydroxybenzotriazole); HPLC (High Performance LiquidChromatography); h (hour); LC (liquid Chromatography); LDA (lithiumdiisopropylamine); MeOH (methanol); min (minute); mL (milliliter); mmol(millimole); MS (Mass spectroscopy); NBS (N-bromosuccinimide); NMR(Nuclear Magnetic Resonance); O/N (overnight); PE (Petroleum Ether); RT(room temperature); TBDMS (tert-Butyldimethylsilyl); TEA(triethylamine); TFA (trifluoroacetic acid); THF (tetrahydofurane); TMS(trimethylsilyl). UPLC/MS analyses were performed on a Waters AquityHwith SQ detector (ESI) and LC/MS on an Agilent 1200 Series with aquadupole detector or a SHIMADZU LC-MS machine consisting of an UFLC20-AD system and a LCMS 2020 MS detector.

The microwave reactions were conducted using Biotage Initiator MicrowaveSynthesizer using standard protocols that are known in the art.

The compounds of the invention were prepared from readily availablestarting materials by several synthetic approaches. Examples ofsynthetic pathways are described below in the examples. Unless otherwisestated, compounds of the invention obtained as a racemic mixture can beseparated to provide an enantiomerically enriched mixture or a pureenantiomer.

The commercially available starting materials used in the followingexperimental description were purchased from Sigma-Aldrich or Fisherunless otherwise reported.

Intermediate 1: tert-butyl(1-(5-bromo-4-cyanopyrimidin-2-yl)-4-methylpiperidin-4-yl)carbamate Step1: tert-butyl(1-(4-cyanopyrimidin-2-yl)-4-methylpiperidin-4-yl)carbamate

A solution of 2-chloropyrimidine-4-carbonitrile (2 g, 14.3 mmol), cesiumcarbonate (11.62 g, 35.7 mol) and tert-butyl(4-methylpiperidin-4-yl)carbamate (3.38 g, 15.8 mmol) in DMF (30 mL) wasstirred overnight at 110° C. The reaction mixture was filtered through acelite pad. The pad was washed with EtOAc (50 mL) and filtrate waswashed with brine. Organic layer was dried over magnesium sulfate,filtered and concentrated. Purification by flash chromatography oversilica (PE: EtOAc, gradient from 100:0 to 50:50) afforded the titlecompound as a white solid (2 g, 66%). 1H NMR (400 MHz, DMSO-d6): 8.61(s, 1H), 7.10 (s, 1H), 6.60 (brs, 1H), 4.06 (m, 2H), 3.38 (m, 2H), 2.07(m, 2H), 1.42 (m, 2H), 1.39 (s, 9H), 1.25 (s, 3H).

Step 2: tert-butyl(1-(5-bromo-4-cyanopyrimidin-2-yl)-4-methylpiperidin-4-yl)carbamate

To a solution of tert-butyl(1-(4-cyanopyrimidin-2-yl)-4-methylpiperidin-4-yl)carbamate (2 g, 6.31mmol) in anhydrous acetonitrile (30 mL) was added N-bromosuccinimide(1.2 g, 6.93 mmol) portion wise at 0° C. The reaction mixture wasstirred at room temperature for 1 h then quenched with ice and extractedwith EtOAc (50 mL). The organic layer was dried over sodium sulphate,filtered and concentrated. Purification by flash chromatography oversilica (PE: EtOAc, gradient from 100:0 to 85:15) afforded the titlecompound as a white solid (2 g, 80%). 1 H NMR (400 MHz, DMSO-d6): 8.75(s, 1H), 6.66 (brs, 1H), 4.01 (m, 2H), 3.35 (m, 2H), 2.08 (m, 2H), 1.43(m, 2H), 1.39 (s, 9H), 1.22 (s, 3H).

Intermediate 2: tert-butylN-[1-(4-amino-5-bromo-6-carbamoylpyrimidin-2-yl)-4-methylpiperidin-4-yl]carbamateStep 1: tert-butylN-[1-(4-amino-6-carbamoylpyrimidin-2-yl)-4-methylpiperidin-4-yl]carbamate

A mixture of 6-amino-2-chloropyrimidine-4-carboxamide (700 mg, 3.20mmol), tert-butyl N-(4-methylpiperidin-4-yl)carbamate (1.3 g, 5.76mmol), TEA (822 mg, 7.72 mmol) in acetonitrile (11 mL) was heated at 80°C. for 18 h in a sealed tube. Solvent was then removed under reducedpressure and the crude was directly purified by flash chromatography onsilica (PE:EtOAc, 90:10) to give the title compound as a yellow solid(1.2 g, 100%). LC/MS (M+1): 351.2.

Step 2: tert-butylN-[1-(4-amino-5-bromo-6-carbamoylpyrimidin-2-yl)-4-methylpiperidin-4-yl]carbamate

NBS (243 mg, 1.30 mmol) was added portion wise to a solution oftert-butylN-[1-(4-amino-6-carbamoylpyrimidin-2-yl)-4-methylpiperidin-4-yl]carbamate(400 mg, 1.14 mmol) in DMF (6 mL) maintained at 0° C. The reactionmixture was stirred at room temperature for 1 h then quenched with iceand extracted with EtOAc. The organic layer was dried over sodiumsulfate, filtered and concentrated to give the title compound as yellowsolid (420 mg, 80%). LC/MS (M+1): 429.2.

Intermediate 3: Methyl5-bromo-2-(4-{[(tert-butoxy)carbonyl]amino}-4-methylpiperidin-1-yl)pyrimidine-4-carboxylate

A mixture of methyl 5-bromo-2-chloropyrimidine-4-carboxylate (300 mg,1.13 mmol), tert-butyl N-(4-methylpiperidin-4-yl)carbamate (307 mg, 1.36mmol) and TEA (0.2 mL) in ACN (3 mL) was stirred for 2 h at 80° C. in asealed tube. Solvent was then removed under reduced pressure and thecrude was purified by flash chromatography on silica (PE:EtOAc, 73:27)to give the title compound as a yellow solid (495 mg, 96%). LC/MS (M+1):429.2.

Intermediate 4:6-Amino-5-(2,3-dichloro-phenyl)-2-methanesulfonyl-pyrimidine-4-carbonitrileStep 1: 6-amino-2-(methylsulfanyl)pyrimidine-4-carbonitrile

A mixture of 6-chloro-2-(methylsulfanyl)pyrimidin-4-amine (50 g, 285mmol), KCN (37.1 g, 569 mmol), Pd₂(dba)₃(15.6 g, 17.1 mmol), DPPF (12.6g, 22.8 mmol) and tributyl(chloro)stannane (5.56 g, 17.1 mmol) in ACN(500 mL) was stirred at 15° C. for 30 min, and then heated to 80° C. for16 h. The mixture was cooled to room temperature, poured into water (2.0L) and extracted with EtOAc (1.5 L). The organic layer was washed withwater (1.5 L), dried over sodium sulfate, filtered and concentrated.Purification by flash chromatography on silica (PE/EtOAc/DCM, gradientfrom 8/1/0 to 4/1/1, with 0.1% NH4OH) afforded the title compound as anoff-white solid (28.6 g, 53%). ¹H NMR (400 MHz DMSO-d₆): 7.62 (brs, 2H),6.63 (s, 1H), 2.40 (s, 3H).

Step 2: 6-amino-5-bromo-2-(methylsulfanyl)pyrimidine-4-carbonitrile

NBS (11.2 g, 62.9 mmol) was added portion-wise to a solution of6-amino-2-(methylsulfanyl)pyrimidine-4-carbonitrile (10.0 g, 60.2 mmol)in DMF (90 mL) maintained at 5° C. The reaction mixture was then stirredat the same temperature for 1 h. It was poured into water (300 mL) andextracted with EtOAc (300 mL). The organic layer was washed with 0.5MNaHCO₃ solution (300 mL×2), dried over sodium sulfate, filtered andconcentrated to give the title compound as a yellow solid (7.78 g,52.7%).

Step 3:6-amino-5-(2,3-dichlorophenyl)-2-(methylsulfanyl)pyrimidine-4-carbonitrile

A mixture of 6-amino-5-bromo-2-(methylsulfanyl)pyrimidine-4-carbonitrile(1.55 g, 6.32 mmol), 2,3-dichlorophenyl)boronic acid (3.02 g, 15.8mmol), XPhos Palladacycle Gen 3 (267 mg, 316 umol) and K₃PO₄ (4.03 g,18.9 mmol) in 1,4-dioxane (15 mL) and H₂O (3 mL) was stirred undernitrogen at 95° C. for 16 h. The mixture was cooled to room temperature,diluted with DCM (20 mL) and filtered. The filtrate was concentratedunder vacuum and purified by RP-MPLC (TFA condition) to give the titlecompound as a yellow solid (1.01 g, 48%) ¹H NMR (400 MHz, CDCl₃): 7.65(dd, J=1.2, 8.0 Hz, 1H), 7.41 (t, J=7.6 Hz, 1H), 7.29 (dd, J=7.6, 8.0Hz, 1H), 5.04 (br, 2H), 2.57 (s, 3H). LC/MS (M+1): 311.1.

Step 4:6-Amino-5-(2,3-dichloro-phenyl)-2-methanesulfonyl-pyrimidine-4-carbonitrile

A solution of mCPBA (2.83 g; 12.65 mmol) in DCM (40 mL) was added to asolution of6-amino-5-(2,3-dichlorophenyl)-2-(methylsulfanyl)pyrimidine-4-carbonitrile(1.97 g; 6.32 mmol) in DCM (40 mL) maintained at 0° C. The reactionmixture was stirred at RT for 2 h, then cooled down to 0° C. before theaddition of another solution of mCPBA (1.42 g; 6.32 mmol) in DCM (20 mL)to obtain complete conversion.

Reaction mixture was stirred at RT for another 2 h. It was then filteredto remove the white precipitate. Filtrate was concentrated, dissolvedagain in DCM, filtrated and concentrated. Purification by flashchromatography on silica (hexane:EtOAc, gradient from 60:40 to 80:20)afforded the title compound as a white solid (1.5 g, 69%). 1H NMR (400MHz, DMSO-d6) δ 8.73 (s, 1H), 7.85 (dd, J=6.1, 3.5 Hz, 1H), 7.70 (s,1H), 7.63-7.55 (m, 2H), 3.37 (s, 3H). LC/MS (M+1): 342.9.

Intermediate 5:{1-[4-Amino-6-cyano-5-(2,3-dichloro-phenyl)-pyrimidin-2-yl]-4-methyl-piperidin-4-yl}-carbamicacid tert-butyl ester

A solution of tert-butyl (4-methylpiperidin-4-yl)carbamate (Synthonix;62 mg; 0.29 mmol) and potassium carbonate (101 mg; 0.73 mmol) in ACN(0.50 mL) and DMF (0.50 mL) was stirred at room for 10 min before theaddition of6-Amino-5-(2,3-dichloro-phenyl)-2-methanesulfonyl-pyrimidine-4-carbonitrile(Intermediate 4; 50 mg; 0.15 mmol). The reaction mixture was then heatedat 100° C. for 66 h. It was diluted with EtOAc (40 mL) and washed withwater (2×10 mL) and brine (10 mL). Organic layer was dried over sodiumsulfate, filtered and concentrated. Purification by flash chromatographyon silica (hexane: EtOAc, gradient from 95:5 to 40:60) afforded thetitle compound as a white foam 1H NMR (400 MHz, DMSO-d6) 7.72 (dd,J=8.0, 1.6 Hz, 1H), 7.45 (t, J=7.8 Hz, 1H), 7.38 (dd, J=7.7, 1.6 Hz,1H), 6.56 (s, 2H), 4.08-3.93 (m, 2H), 3.40-3.24 (m, 2H), 2.04 (d, J=13.5Hz, 2H), 1.46-1.32 (m, 11H), 1.26 (s, 3H).

Intermediate 6:6-Amino-2-(4-amino-4-methyl-piperidin-1-yl)-5-(2,3-dichloro-phenyl)-pyrimidine-4-carboxylicacid

A solution of tert-butylN-[1-[4-amino-6-cyano-5-(2,3-dichlorophenyl)pyrimidin-2-yl]-4-methylpiperidin-4-yl]carbamate(intermediate 5; 370 mg, 0.628 mmol) and NaOH (132 mg, 3.139 mmol) inwater (5 mL) was stirred for 16 h at 100° C. in an oil bath. The pH wasadjusted to 4 by addition of a 1M HCl solution and the solution wasconcentrated under reduced pressure. The residue was dissolved in MeOH(10 mL) and purified by flash chromatography C18 silica gel (ACN:water—0.5% HCl), gradient from 10% to 50% in 10 min) to afford the titlecompound as a yellow solid (250 mg, 94%). mp: 179-181° C. 1H NMR (400MHz, DMSO-d6) 8.18 (s, 3H), 7.63-7.57 (m, 1H), 7.39-7.31 (m, 2H), 7.22(s, 1H), 7.15 (d, J=7.5 Hz, 1H), 7.09 (s, 1H), 4.27 (d, J=13.9 Hz, 1H),2.55 (s, OH), 1.71 (s, 4H), 1.39 (s, 3H). LC/MS (M+1): 396.1.

Intermediate 7:6-amino-2-(4-{[(tert-butoxy)carbonyl]amino)-}4-methylpiperidin-1-yl)-5-(2,3-dichlorophenyl)pyrimidine-4-carboxylicacid

A solution of tert-butylN-[1-[4-amino-6-cyano-5-(2,3-dichlorophenyl)pyrimidin-2-yl]-4-methylpiperidin-4-yl]carbamate(Intermediate 5, 200 mg, 0.34 mmol) in aq. NaOH (1N solution, 4 mL) andEtOH (2 mL) was heated at 100° C. for 16 h. It was then diluted withwater and extracted with EtOAc (3×20 mL). Combined organic layers werethen washed with brine, dried over magnesium sulfate, filtered andconcentrated. Purification by flash chromatography on silica(EtOAc:MeOH, 70:30) afforded the title compound as a white solid (140mg, 69%). LC/MS (M+1): 496.1.

Intermediate 8: tert-butylN-[1-(5-bromo-4-cyano-6-methylpyrimidin-2-yl)-4-methylpiperidin-4-yl]carbamateStep 1: tert-butylN-[1-(4-cyano-6-methylpyrimidin-2-yl)-4-methylpiperidin-4-yl]carbamate

A solution of 2-chloro-6-methylpyrimidine-4-carbonitrile (1 g, 6.2mmol), tert-butyl N-(4-methylpiperidin-4-yl)carbamate (1.7 g, 7.4 mmol)and TEA (0.1 mL) in ACN (15 mL) was heated at 80° C. for 2 h. Thesolvent was removed under reduced pressure and the crude was purified byflash chromatography (PE:EtOAc, gradient from 100:0 to 50:50) to affordthe title compound as a yellow solid (1.9 g, 92%). LC/MS (M+1): 332.2.

Step 2: tert-butylN-[1-(5-bromo-4-cyano-6-methylpyrimidin-2-yl)-4-methylpiperidin-4-yl]carbamate

A solution of tert-butylN-[1-(4-cyano-6-methylpyrimidin-2-yl)-4-methylpiperidin-4-yl]carbamate(1.9 g, 5.7 mmol) and NBS (1.6 g, 8.5 mmol) in DMF (10 mL) was stirredat room temperature for 1 h. The reaction mixture was then diluted withwater (200 mL) and extracted with EtOAc (3×200 mL). Combined organiclayers were washed with brine, dried over anhydrous sodium sulfate,filtered and concentrated to give the title compound as a yellow solid(2.3 g, 96%). LC/MS (M+1): 410.2.

Intermediate 9:7-chloro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole

A mixture of 6-bromo-7-chloro-1H-indazole (300 mg, 1.23 mmol),Pd(dppf)Cl₂·DCM (53 mg, 0.062 mmol), BPD (497 mg, 1.859 mmol) and KOAc(381 mg, 3.7 mmol) in dioxane (5 mL) flushed with nitrogen was heated at120° C. for 2 h in a sealed tube. Solvent was then removed under reducedpressure and the residue was purified by flash chromatography on silica(PE: EtOAc, 50:50) to afford the title compound as a yellow oil (300 mg,44%). LC/MS (M+1): 279.2.

Intermediate 10:6-amino-5-(7-chloro-1H-indazol-6-yl)-2-methanesulfonyl-pyrimidine-4-carbonitrile

The title compound was obtained following a procedure similar to the onedescribed for intermediate 4 but starting from7-chloro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole(intermediate 9) as a yellow oil. LC/MS (M+1): 349.0.

Intermediate 11: tert-butylN-[(3S,4S)-8-(5-bromo-4-cyano-6-methylpyrimidin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-yl]carbamateStep 1: tert-butylN-[(3S,4S)-8-(4-cyano-6-methylpyrimidin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-yl]carbamate

A solution of 2-chloro-6-methylpyrimidine-4-carbonitrile (106 mg; 0.69mmol), tert-butylN-[(3S,4S)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-yl]carbamate (125 mg;0.46 mmol) and DIEA (0.4 mL, 2.31 mmol) in anhydrous DMSO (2.5 mL) wasstirred for 24 h at 70° C. The reaction mixture was diluted with water(10 mL) and EtOAc (25 mL). Organic layer was washed with water (2×) andbrine, dried over sodium sulfate, filtered and concentrated.Purification by flash chromatography on silica (Hexane:EtOAc, gradientfrom 95:5 to 20:80) afforded the title compound as a yellow foam (175mg, 98%). 1H NMR (Bruker 400 MHz, DMSO-d6): 7.03 (s, 1H), 6.98 (d,J=10.4 Hz, 1H), 4.23-4.11 (m, 1H), 3.88 (dd, J=10.5, 5.1 Hz, 1H),3.85-3.78 (m, 1H), 3.78-3.63 (m, 3H), 3.63-3.53 (m, 1H), 3.50 (d, J=8.4Hz, 1H), 2.34 (s, 3H), 1.69-1.51 (m, 3H), 1.51-1.42 (m, 1H), 1.39 (s,9H), 1.02 (d, J=6.3 Hz, 3H); LC/MS (M+1): 388.2.

Step 2: tert-butylN-[(3S,4S)-8-(5-bromo-4-cyano-6-methylpyrimidin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-yl]carbamate

A solution of N-Bromosuccinimide (121 mg; 0.68 mmol) in DMF (1.75 mL)was added slowly to a solution of tert-butylN-[(3S,4S)-8-(4-cyano-6-methylpyrimidin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-yl]carbamate(175 mg; 0.45 mmol) in DMF (1.75 mL) maintained at 0° C. The reactionmixture was stirred at RT for 2 h. It was then diluted with EtOAc (50mL) and washed with water (2×25 mL) and brine (25 mL), dried over sodiumsulfate, filtered and concentrated. Purification by flash chromatographyon silica (Hexane:EtOAc; gradient from 95:5 to 50:50) to afford thetitle compound as a white foam (158 mg, 75%). 1H NMR (Bruker 400 MHz,DMSO-d6): 6.99 (d, J=10.5 Hz, 1H), 4.22-4.12 (m, 1H), 3.88 (dd, J=10.5,5.1 Hz, 1H), 3.85-3.76 (m, 1H), 3.76-3.63 (m, 3H), 3.60-3.47 (m, 2H),2.48 (s, 3H), 1.69-1.52 (m, 3H), 1.52-1.43 (m, 1H), 1.40 (s, 9H), 1.03(d, J=6.3 Hz, 3H); LC/MS (M+1): 466.1, 468.1.

Intermediate 12: tert-butylN-[(1R)-8-(4-cyano-6-methylpyrimidin-2-yl)-3,3-difluoro-8-azaspiro[4.5]decan-1-yl]carbamateStep 1: tert-butylN-[(1R)-8-(4-cyano-6-methylpyrimidin-2-yl)-3,3-difluoro-8-azaspiro[4.5]decan-1-yl]carbamate

The title compound was obtained following procedure described forintermediate 12, step 1 but starting from2-chloro-6-methylpyrimidine-4-carbonitrile (99 mg; 0.65 mmol) andtert-butyl N-[(1R)-3,3-difluoro-8-azaspiro[4.5]decan-1-yl]carbamate (125mg; 0.43 mmol) as a yellow foam (172 mg, 98%).1H NMR (400 MHz, DMSO-d6):7.09-7.00 (m, 2H), 4.51-4.26 (m, 2H), 3.85 (q, J=9.3 Hz, 1H), 3.18-2.94(m, 2H), 2.48-2.36 (m, 2H), 2.34 (s, 3H), 2.31-1.95 (m, 2H), 1.62-1.38(m, 4H), 1.34 (s, 9H), LC/MS (M+1): 408.1

Step 2: tert-butylN-[(1R)-8-(5-bromo-4-cyano-6-methylpyrimidin-2-yl)-3,3-difluoro-8-azaspiro[4.5]decan-1-yl]carbamate

The title compound was obtained following procedure described forintermediate 12, step 2 but starting from tert-butylN-[(1R)-8-(4-cyano-6-methylpyrimidin-2-yl)-3,3-difluoro-8-azaspiro[4.5]decan-1-yl]carbamate(170.00 mg; 0.42 mmol) as a yellow solid (150 mg, 74%). LC/MS (M+1):486.1, 488.1.

Intermediate 13: tert-butylN-[(1R)-8-(5-bromo-4-cyano-6-methylpyrimidin-2-yl)-8-azaspiro[4.5]decan-1-yl]carbamateStep 1: tert-butylN-[(1R)-8-(4-cyano-6-methylpyrimidin-2-yl)-8-azaspiro[4.5]decan-1-yl]carbamate

The title compound was obtained following procedure described forintermediate 12, step 1 but starting from2-chloro-6-methylpyrimidine-4-carbonitrile (258 mg; 1.68 mmol) andtert-butyl N-[(1R)-8-azaspiro[4.5]decan-1-yl]carbamate (214 mg; 0.84mmol) as a yellow foam (295 mg, 94%). 1H NMR (Bruker 400 MHz, DMSO-d6):7.00 (s, 1H), 6.73 (d, J=9.3 Hz, 1H), 4.45-4.13 (m, 2H), 3.57 (q, J=8.3Hz, 1H), 3.24-3.06 (m, 2H), 2.34 (s, 3H), 1.93-1.78 (m, 1H), 1.78-1.58(m, 2H), 1.58-1.40 (m, 4H), 1.41-1.20 (m, 12H). LC/MS (M+1): 372.0.

Step 2: tert-butylN-[(1R)-8-(5-bromo-4-cyano-6-methylpyrimidin-2-yl)-8-azaspiro[4.5]decan-1-yl]carbamate

The title compound was obtained following procedure described forintermediate 12, step 2 but starting from tert-butylN-[(1R)-8-(4-cyano-6-methylpyrimidin-2-yl)-8-azaspiro[4.5]decan-1-yl]carbamate(295 mg; 0.79 mmol) as a yellow foam (270 mg, 75%). LC/MS: 450.0, 452.0.

Intermediate 14: (3R)-3H-spiro[1-benzofuran-2,4′-piperidin]-3-aminehydrochloride Step 1: 2-(2-fluorophenyl)-1,3-dithiane

BF₃·Et₂O (25 mL, 197 mmol) was added to a solution of2-fluoro-benzaldehyde (10.0 g, 76.5 mmol) and 1,3-propanedithiol (17.4g, 153.1 mmol) in DCM (100 mL) at 25° C. The resulting mixture wasstirred for 16 h at 25° C. It was then concentrated under vacuum andpurified by flash chromatography on silica (PE:EtOAc, 5:1) to afford thetitle compound as an off-white solid (16.0 g, 95%). LC/MS (M+1): 215

Step 2: 4-(2-fluorobenzoyl)piperidin-4-ol

A solution of 2-(2-fluorophenyl)-1,3-dithiane (10.0 g, 40.7 mmol) in THF(5 mL) was added to a solution of LDA in THF (41 mL, 2M) maintained at−78° C. under nitrogen atmosphere. The resulting mixture was stirred at−20° C. for 30 min. Then a solution of tert-butyl4-oxopiperidine-1-carboxylate (12.8 g, 61.1 mmol) in THF (5 mL) wasadded dropwise at −78° C. After stirring for 1 h at −78° C., thereaction mixture was poured into a saturated solution of NH₄Cl (100 mL)and extracted with EtOAc (3×100 mL). Combined organic layers were washedwith brine (1×100 ml), dried over anhydrous Na₂SO₄, filtered andconcentrated. Purification by flash chromatography on silica (PE:EtOAc,1:1) afforded tert-butyl4-[2-(2-fluorophenyl)-1,3-dithian-2-yl]-4-hydroxypiperidine-1-carboxylateas an off-white solid (15.0 g, 78%), LC/MS (M+1): 314.

A solution of tert-butyl4-[2-(2-fluorophenyl)-1,3-dithian-2-yl]-4-hydroxypiperidine-1-carboxylate(15.0 g, 47.9 mmol), TBAB (4.63 g, 14.4 mmol), Pyridine hydrobromide(15.3 g, 95.8 mmol) and pyridine (7.7 mL, 95.8 mmol) in DCM (200 mL) andH₂O (40 mL) was stirred for 16 h at 25° C. The resulting mixture wasconcentrated under reduced pressure and purified by flash chromatographyon silica (DCM:MeOH, 1;1) to afford the title compound as a brown oil(10.4 g, 97%). LC/MS (M+1): 224.

Step 3: Spiro[1-benzofuran-2,4′-piperidin]-3-one

A solution of 4-(2-fluorobenzoyl)piperidin-4-ol (10.0 g, 40.3 mmol),t-BuOK (9.52 g, 80.6 mmol) and dioxane (100 mL) was stirred for 2 h at120° C. The reaction mixture was cooled to room temperature, filteredand concentrated under vacuum. The residue was purified by flashchromato graphy on silica (DCM:MeOH, 1:1) to afford thetitle compound asa brown solid (8.0 g, 96%). LC/MS (M1): 204.

Step 4:(S)-2-methyl-N-[1′-[(S)-2-methylpropane-2-sulfinyl]spiro[1-benzofuran-2,4′-piperidin]-3-ylidene]propane-2-sulfinamide

A mixture of Ti(OEt)₄ (50 mL), (R)-2-methylpropane-2-sulfinamide (18.0g, 140.7 mmol) and spiro[1-benzofuran-2,4-piperidin]-3-one (5.00 g, 23.4mmol) was stirred for 16 h at 90° C. it was then diluted with water (120mL) and extracted with EtOAc (3×120 mL). The combined organic layerswere washed with brine (1×100 mL), dried over anhydrous Na₂SO₄, filteredand concentrated. Purification by flash chromatography on silica(PE:EtOAc, 1:1) afforded the title compound as a yellow solid (6.0 g,60%). LC/MS (M+1): 411.

Step 5:(S)-2-methyl-N-[(3S)-1′-[(S)-2-methylpropane-2-sulfinyl]-3H-spiro[1-benzofuran-2,4′-piperidin]-3-yl]propane-2-sulfinamide

NaBH₄ (1.87 g, 46.9 mmol) was added to a solution of(S)-2-methyl-N-[1-[(S)-2-methylpropane-2-sulfinyl]spiro[1-benzofuran-2,4-piperidin]-3-ylidene]propane-2-sulfinamide(4.00 g, 9.38 mmol) in THF (100 mL) and H₂O (2.00 mL) at −50° C. Theresulting mixture was stirred for 2 h at 25° C. It was then quenchedwith saturated NH₄Cl aqueous at 0° C. and extracted with EtOAc (3×100mL). Combined organic layers were washed with brine (1×100 mL), driedover anhydrous Na₂SO₄, filtered and concentrated. Purification by flashchromatography on silica (PE: EtOAc, 1;1) afforded the title compound asa yellow solid (2 g, 52%). LC/MS (M+1): 413.

Step 5: (3R)-3H-spiro[1-benzofuran-2,4′-piperidin]-3-amine hydrochloride

A mixture of HCl/MeOH (10 mL, 6M) and(S)-2-methyl-N-[(3S)-1-[(S)-2-methylpropane-2-sulfinyl]-3H-spiro[1-benzofuran-2,4-piperidin]-3-yl]propane-2-sulfinamide(700 mg, 1.70 mmol) was stirred for 2 h at 25° C. The resulting mixturewas concentrated under reduced pressure. The solids were collected byfiltration and washed with Et₂O (3×10 mL) to give the title compound asan off-white solid (300 mg, 85%). LC/MS (M+1): 205.

Intermediate 15: 3H-spiro[furo[2,3-b]pyridine-2,4′-piperidin]-3-amineStep 1: 3-(1,3-dithian-2-yl)-2-fluoropyridine

To a solution of 2-fluoropyridine-3-carbaldehyde (46.0 g, 349.3 mmol)and 1,3-propanedithiol (43.8 g, 384.2 mmol) in DCM (500 mL) was addedBF₃·Et₂O (29 mL, 107.6 mmol, 0.31 equiv, 47%) dropwise at roomtemperature. The resulting mixture was stirred for 16 h at roomtemperature. The reaction was quenched with saturated NaHCO₃ (200 mL)and extracted with EtOAc (3×200 mL). The combined organic layers weredried over anhydrous Na₂SO₄, filtered and concentrated. Purification byflash chromatography on silica (PE:EtOAc, 10:1) afforded the titlecompound as a white solid (59 g, 63%). LC/MS (M+1): 216.

Step 2: Tert-butyl4-[2-(2-fluoropyridin-3-yl)-1,3-dithian-2-yl]-4-hydroxypiperidine-1-carboxylate

A solution of LDA (240 mL, 2M in THF) was added dropwise to a solutionof 3-(1,3-dithian-2-yl)-2-fluoropyridine (59.0 g, 220.3 mmol) in THF(150 mL) maintained at −78° C. The resulting mixture was then stirredfor 60 min at −20° C. before the addition of a solution of tert-butyl4-oxopiperidine-1-carboxylate (92.4 g, 440.6 mmol) in THF (30 mL) at−78° C. The resulting mixture was stirred for an additional 1 h at −78°C. and quenched with saturated NH₄Cl (500 mL) at 0° C. It was extractedwith EtOAc (3×300 mL). The combined organic layers were dried overanhydrous Na₂SO₄, filtered and concentrated. Purification by flashchromatography on silica (PE:EtOAc, 5:1) afforded the title compound asa white solid ((80 g, 87%). LC/MS: 359 (M+H−56)

Step 3: Tert-butyl4-(2-fluoropyridine-3-carbonyl)-4-hydroxypiperidine-1-carboxylate

A solution of tert-butyl4-[2-(2-fluoropyridin-3-yl)-1,3-dithian-2-yl]-4-hydroxypiperidine-1-carboxylate(90.0 g, 213.6 mmol), TBAB (21.7 g, 64.1 mmol), 2|{circumflex over( )}[2]-tribromane.pyridine (143.8 g, 427.2 mmol) and pyridine (27.2 mL,320.4 mmol, 1.50 equiv) in DCM (1 L) and H₂O (200 mL) was stirred for 10h at room temperature. The reaction mixture was then extracted with DCM(3×300 mL). The combined organic layers were dried over anhydrousNa₂SO₄, filtered and concentrated. Purification by flash chromatographyon silica (PE:EtOAc, 2:1) afforded the title compound as a yellow solid(50.0 g, 71%). LC/MS: 269 (M+H−56).

Step 4: Tert-butyl3-oxospiro[furo[2,3-b]pyridine-2,4-piperidine]-1-carboxylate

t-BuOK (6.51 g, 55.1 mmol) was added to a solution of tert-butyl4-(2-fluoropyridine-3-carbonyl)-4-hydroxypiperidine-1-carboxylate (17.0g, 50.1 mmol) in dioxane (170 mL) at room temperature. After stirringfor 2 h, the resulting mixture was poured into water (200 mL) andextracted with EtOAc (3×200 mL). The combined organic layers were driedover anhydrous Na₂SO₄, filtered and concentrated. Purification by flashchromatography on silica (PE:EtOAc 5:1) afforded the title compound as awhite solid (8.5 g, 53%). LC/MS: 249 (M+H−56).

Step 5: Tert-butyl3-[[(R)-2-methylpropane-2-sulfinyl]imino]spiro[furo[2,3-b]pyridine-2,4′-piperidine]-1′-carboxylate

A mixture of tert-butyl3-oxospiro[furo[2,3-b]pyridine-2,4-piperidine]-1-carboxylate (8.50 g,26.8 mmol), (R)-2-methylpropane-2-sulfinamide (20.5 g, 160.7 mmol) andTi(OEt)₄ (60 mL) was stirred for 2 h at 90° C. The resulting mixture wascooled to room temperature and poured into with H₂O (150 mL). it wasfiltered, and the filtrate was extracted with EtOAc (3×150 mL). Thecombined organic layers were dried over anhydrous Na₂SO₄, filtered andconcentrated. Purification by flash chromatography on silica (PE: EtOAc,5:1) afforded the title compound as a yellow solid (11 g, 96%). LC/MS(M+1): 408.0.

Step 6:Tert-butyl-3-[[(S)-2-methylpropane-2-sulfinyl]amino]-3H-spiro[furo[2,3-b]pyridine-2,4′-piperidine]-1′-carboxylate

Sodium borohydride (4.66 g, 117 mmol) was added in portions to a stirredsolution of tert-butyl3-[[(R)-2-methylpropane-2-sulfinyl]imino]spiro[furo[2,3-b]pyridine-2,4-piperidine]-1-carboxylate(10.0g, 23.4 mmol) in THF (100 mL) and MeOH (100 mL) at −50° C. The resultingmixture was stirred for 1 h at −50° C. and quenched with water (10 mL).Solvent was removed under reduced pressure, the mixture was diluted withwater (100 mL) and extracted with ethyl acetate (3×100 mL). The combinedorganic layers were washed with brine (100 mL), dried over anhydroussodium sulfate, filtered and concentrated to afford the title compoundas a yellow solid (10 g, 62%). LC/MS (M+1): 410.0.

Step 7: 3H-spiro[furo[2,3-b]pyridine-2,4′-piperidin]-3-amine

A solution of HCl (gas) in 1,4-dioxane (100 mL) was added dropwise to asolution oftert-butyl-3-[[(S)-2-methylpropane-2-sulfinyl]amino]-3H-spiro[furo[2,3-b]pyridine-2,4′-piperidine]-1′-carboxylate(10.0 g, 24.4 mmol) in DCM (60 mL) maintained at 0° C. After stirringfor 1 h at room temperature, the resulting mixture was concentratedunder reduced pressure. The resulting HCl salt was loaded onto theSiliaBond Propylsulfonic Acid (SCX-2) resin, which was pre-wetted withmethanol, eluting with methanol until no HCl was detected. Then the freeamine was washed out with 7M NH₃ in methanol. The eluent wasconcentrated under vacuum to give the title compound as an orange oil(4.0 g, 77.7%). LC/MS (M+1): 206.

Intermediate 16:(4S)-4,6-dihydrospiro[cyclopenta[d][1,3]thiazole-5,4′-piperidin]-4-amineStep 1: tert-butyl(4Z)-2-chloro-4-{[(R)-2-methylpropane-2-sulfinyl]imino}-4,6-dihydrospiro[cyclopenta[d][1,3]thiazole-5,4′-piperidine]-1′-carboxylate

A mixture of tert-butyl2-chloro-4-oxo-6H-spiro[cyclopenta[d][1,3]thiazole-5,4-piperidine]-1-carboxylate(300 mg, 0.845 mmol) and (R)-2-methylpropane-2-sulfinamide (647 mg, 5.07mmol) in Ti(OEt)₄ (3.39 g, 14.1) was stirred for 19 h at 90° C. undernitrogen atmosphere. The reaction was then quenched by the additionwater (50 mL) and filtered. The filtrate was extracted with EtOAc (3×150mL). Combined organic layers were dried over sodium sulfate, filteredand concentrated. Purification by flash chromatography on silica (PE:EtOAc, gradient from 1:0 to 1:1) afforded the title compound as a yellowsolid (280 mg, 74%). LC/MS (M+1): 446.1.

Step 2: tert-butyl(4S)-2-chloro-4-{[(R)-2-methylpropane-2-sulfinyl]amino}-4,6-dihydrospiro[cyclopenta[d][1,3]thiazole-5,4′-piperidine]-1′-carboxylate

Sodium borohydride (70 mg, 1.78 mmol) was added portion-wise to asolution oftert-butyl-(4Z)-2-chloro-4-[[(R)-2-ethylpropane-2-Ifinyl]imino]-6H-spiro[cyclopenta[d][1,3]thiazole-5,4-piperidine]-1-carboxylate(400 mg, 0.892 mmol) in THF (4.4 mL) and water (1.3 mL) maintained at−50° C. under argon atmosphere. The resulting mixture was stirred for 2h at −50° C. under argon atmosphere, quenched by the addition of water(50 mL) and filtered. The filtrate was extracted with EtOAc (3×50 mL).Combined organic layers were dried over sodium sulfate, filtered andconcentrated. Purification by flash chromatography on silica (PE:EtOAc,gradient from 1:0 to 0:1) afforded the title compound as a yellow solid(200 mg, 50%), LC/MS (M+1): 448.1.

Step 3: tert-butyl(4S)-4-{[(R)-2-methylpropane-2-sulfinyl]amino}-4,6-dihydrospiro[cyclopenta[d][1,3]thiazole-5,4′-piperidine]-1′-carboxylate

A suspension of tert-butyl(4S)-2-chloro-4-[[(R)-2-methylpropane-2-sulfinyl]amino]-4,6-dihydrospiro[cyclopenta[d][1,3]thiazole-5,4-piperidine]-1-carboxylate(0.20 g, 0.446 mmol), Pd/C (0.10 g, 0.094 mmol, 10%) in MeOH (10 mL)under H₂ atmosphere was stirred for 12 h at 100° C. The mixture wasfiltered through a celite pad and the filtrate was concentrated to givethe title compound as a yellow sold (130 mg, 66%). LC/MS (M+1):414.2.

Step 4:(4S)-4,6-dihydrospiro[cyclopenta[d][1,3]thiazole-5,4′-piperidin]-4-amine

A solution of tert-butyl(4S)-4-[[(R)-2-methylpropane-2-sulfinyl]amino]-4,6-dihydrospiro[cyclopenta[d][1,3]thiazole-5,4-piperidine]-1-carboxylate(150 mg, 0.337 mmol) in MeOH/HCl (4 mL, 26 mmol, 20%) was stirred for 30min at room temperature. The solvent was removed under reduced pressureand the residue was loaded onto SiliaBond Propylsulfonic Acid (SCX-2)resin, pre-wetted with methanol. The resin was eluted with MeOH and thefree amine was released with MeOH/NH₃ (7M). MeOH was removed underreduced pressure to afford the title compound as an off-white solid (65mg, 89%). LC/MS (M+1): 210.1.

Compound 1:2-(4-amino-4-methylpiperidin-1-yl)-5-(2,3-dichlorophenyl)-pyrimidine-4-carboxamideStep 1: Synthesis of tert-butyl(1-(4-cyano-5-(2,3-dichlorophenyl)pyrimidin-2-yl)-4-methylpiperidin-4-yl)carbamate

A solution of tert-butyl(1-(5-bromo-4-cyanopyrimidin-2-yl)-4-methylpiperidin-4-yl)carbamate(Intermediate 1, 2 g, 5.06 mmol), 2,3-dichlorophenyl boronic acid (0.967g, 5.06 mmol) and cesium carbonate (4.1 g, 12.6 mmol) in dioxane/watermixture (15:5 mL) was degassed with nitrogen for 3 min. Pd(PPh₃)₄(0.58g, 0.51 mmol) was added and the reaction mixture was heated overnight at100° C. under inert atmosphere. The reaction mixture was dissolved inEtOAc (50 mL) and washed with water (30 mL) and brine solution (30 mL).Organic layer was dried over sodium sulphate, filtered and concentrated.Purification by flash chromatography on silica (PE: AcOEt, gradient from100:0 to 80:20) afforded the title compound as a white solid (1.6 g,70%). 1 H NMR (400 MHz, DMSO-d6): 8.68 (s, 1H), 8.80 (dd, J=2.0, 7.6 Hz,1H), 4.56 (m, 2H), 6.69 (brs, 1H), 4.06 (m, 2H), 3.45 (m, 2H), 2.12 (m,2H), 1.48 (m. 2H), 1.40 (s, 9H), 1.27 (s, 3H).

Step 2: tert-butylN-{1-[4-carbamoyl-5-(2,3-dichlorophenyl)pyrimidin-2-yl]-4-methylpiperidin-4-yl}carbamate

To a solution of tert-butyl(1-(4-cyano-5-(2,3-dichlorophenyl)pyrimidin-2-yl)-4-methylpiperidin-4-yl)carbamate(0.2 g, 0.432 mmol) in DMSO (8 mL) was added hydrogen peroxide (0.4 mL,30% in water) and potassium carbonate (0.119 g, 0.86 mmol) at 0° C. .Thereaction mixture was stirred at room temperature for 1 h, then quenchedwith water and extracted with ethyl acetate (2×20 mL). Combined organiclayers were dried over anhydrous sodium sulfate, filtered andconcentrated to afford the title compound (0.18 g, 87%). LC/MS (M+1):480.2.

Step 3:2-(4-amino-4-methylpiperidin-1-yl)-5-(2,3-dichlorophenyl)pyrimidine-4-carboxamidehydrochloride

A solution of HCl (2 mL of a 4M solution in dioxane) was added to asolution of tert-butylN-{1-[4-carbamoyl-5-(2,3-dichlorophenyl)pyrimidin-2-yl]-4-methylpiperidin-4-yl}carbamate(180 mg, 0.375 mmol) in anhydrous dichloromethane (5 mL) maintained at0° C. The reaction mixture was stirred at room temperature for 1 h. Itwas then concentrated under reduced pressure to give the title compoundas a white solid (75 mg, 50%). 1H NMR (400 MHz, DMSO-d6): 8.36 (s, 1H),8.14 (m, 4H), 7.59 (m, 2H), 7.37 (t, J=9.2 Hz, 1H), 7.26 (d, J=7.2 Hz,1H), 4.40 (m, 2H), 3.52 (m, 2H), 1.76 (m, 4H), 1.41 (s, 3H).

Compound 2:6-Amino-2-(4-amino-4-methyl-piperidin-1-yl)-5-(3-chloro-phenyl)-pyrimidine-4-carboxylicacid amide Step 1: tert-butylN-{1-[4-amino-6-carbamoyl-5-(3-chlorophenyl)pyrimidin-2-yl]-4-methylpiperidin-4-yl}carbamate

A mixture of tert-butylN-[1-(4-amino-5-bromo-6-carbamoylpyrimidin-2-yl)-4-methylpiperidin-4-yl]carbamate(Intermediate 2, 250 mg, 0.41 mmol), (3-chlorophenyl)boronic acid (137mg, 0.83 mmol), Pd(PPh₃)₄(34 mg, 0.03 mmol) and sodium carbonate (84 mg,0.75 mmol) in water (2 mL) and dioxane (6 mL) was heated for 30 min at130° C. under inert atmosphere. Solvent was then removed-under reducedpressure and the crude was purified by flash chromatography on silica(PE:EtOAc, 50:50) to give the title compound as a yellow solid (110 mg,47%). LC/MS (M+1): 461.2.

Step 2:6-Amino-2-(4-amino-4-methyl-piperidin-1-yl)-5-(3-chloro-phenyl)-pyrimidine-4-carboxylicacid amide

A solution of tert-butylN-[1-[4-amino-6-carbamoyl-5-(3-chlorophenyl)pyrimidin-2-yl]-4-methylpiperidin-4-yl]carbamate(200 mg, 0.37 mmol) and HCl (0.6 mL of a 1.25 M solution in MeOH) inMeOH (6 mL) was stirred at room temperature for 2 h. Solvent was removedunder reduced pressure and the crude was purified by preparative HPLC(XBridge Prep C18 OBD Column, 5 μm,19*150 mm; mobile phase, Water (10 mMNH₄HCO₃+0.1% NH₄OH) and ACN (gradient from 18% ACN up to 48% in 8 min)to afford the title compound as a white solid (31 mg, 23%). mp: 118-120°C. 1H NMR (300 MHz, CD₃OD); 7.43-7.27 (m, 2H), 7.28-7.20 (m, 1H), 7.16(m, 1H), 4.07-3.95 (m, 2H), 3.70 (m, 2H), 1.58 (m, 4H), 1.25 (d, J=1.3Hz, 3H). LC/MS (M+1): 361.3.

Compound 3:6-Amino-2-(4-amino-4-methyl-piperidin-1-yl)-5-(2,3-dichloro-phenyl)-pyrimidine-4-carboxylicacid amide Step 1:6-Amino-2-(4-amino-4-methyl-piperidin-1-yl)-5-(2,3-dichloro-phenyl)-pyrimidine-4-carbonitrilebis-trifluoroacetate

A solution of{1-[4-Amino-6-cyano-5-(2,3-dichloro-phenyl)-pyrimidin-2-yl]-4-methyl-piperidin-4-yl}-carbamicacid tert-butyl ester (intermediate 5; 34 mg; 0.07 mmol) and TFA (0.34mL) in DCM (0.68 mL) was stirred for 1 h at room temperature. Solventwas then removed under reduced pressure and excess TFA was removed byco-evaporation with toluene to give the title compound a white foam (42mg, 97%). LC/MS (M+1): 377.1

Step 2:6-Amino-2-(4-amino-4-methyl-piperidin-1-yl)-5-(2,3-dichloro-phenyl)-pyrimidine-4-carboxylicacid amide

A solution of6-Amino-2-(4-amino-4-methyl-piperidin-1-yl)-5-(2,3-dichloro-phenyl)-pyrimidine-4-carbonitrilebis-trifluoroacetate (35 mg; 0.06 mmol), sodium hydroxide (0.1 mL of a6M aqueous solution, 0.58 mmol) and hydrogen peroxide (30% weight, 70ul; 0.58 mmol) in DMF (1.40 mL) was heated in a microwave reactor at100° C. for 1 h. Hydrogen peroxide and sodium hydroxide were added twice(same amount) and the reaction mixture heated at 100° C. again to obtainfull conversion. Reaction mixture was filtered through a celite padbefore purification by preparative HPLC (XBridge Prep C-18 OBD 10 uM,30×250. Water (0.1% Ammonium Hydroxide) and ACN, gradient from 30 to 80%in 15 minutes) to afford the title compound as a white amorphous foam(mixture of two atropisomers, 12 mg, 48%). 1H NMR (400 MHz, DMSO-d6)7.70 (s, 1H), 7.51 (dd, J=8.1, 1.6 Hz, 1H), 7.28 (t, J=7.8 Hz, 1H), 7.14(s, 1H), 7.10 (dd, J=7.6, 1.6 Hz, 1H), 6.05 (s, 2H), 3.99-3.87 (m, 2H),3.68-3.54 (m, 2H), 1.47-1.31 (m, 4H), 1.08 (s, 3H). LC/MS (M+1): 395.2.

Compound 26 and 27:(4M)-6-Amino-2-(4-amino-4-methyl-piperidin-1-yl)-5-(2,3-dichloro-phenyl)-pyrimidine-4-carboxylicacid amide and(4P)-6-Amino-2-(4-amino-4-methyl-piperidin-1-yl)-5-(2,3-dichloro-phenyl)-pyrimidine-4-carboxylicacid amide

A mixture of atropisomers 3 (200 mg) was separated by SFC ((R,R)WHELK-014.6×150 mm,5 um,EtOH+0.1% DEA:CO₂, 10-50%).

First elutinq isomer (compound 26): white solid, 76 mg, RT=3.42 min,ed=99.7%, 1H NMR (300 MHz, DMSO-d6): 7.75-7.68 (m, 1H), 7.49 (dd, J=8.0,1.6 Hz, 1H), 7.27 (t, J=7.8 Hz, 1H), 7.15 (s, 1H), 7.08 (dd, J=7.7, 1.6Hz, 1H), 6.07 (s, 2H), 3.96-3.85 (m, 2H), 3.68-3.53 (m, 2H), 1.59 (brs,1H), 1.37 (q, J=4.9, 4.4 Hz, 4H), 1.07 (s, 3H), mp: 126-128° C.

Second elutinq isomer (compound 27): white solid, 76 mg, RT=3.79 min,ed=98.2%, 1H NMR (300 MHz, DMSO-d6) 7.71 (s, 1H), 7.49 (dd, J=8.1, 1.5Hz, 1H), 7.27 (t, J=7.8 Hz, 1H), 7.16 (s, 1H), 7.08 (dd, J=7.7, 1.6 Hz,1H), 3.91 (d, J=13.6 Hz, 2H), 3.61 (dt, J=13.1, 6.4 Hz, 2H), 1.61 (brs,2H), 1.46-1.34 (m, 4H), 1.07 (s, 3H), mp: 130-132° C.

Compound 4:6-Amino-2-(4-amino-4-methyl-piperidin-1-yl)-5-(3-fluoro-phenyl)-pyrimidine-4-carboxylicacid amide

The title compound was obtained following procedure described above butstarting from tert-butylN-[1-(4-amino-5-bromo-6-carbamoylpyrimidin-2-yl)-4-methylpiperidin-4-yl]carbamate(Intermediate 2, 500 mg, 1.1 mmol) and (3-fluorophenyl)boronic acid (243mg, 1.7 mmol) as an off-white solid. 1H NMR (400 Mz, DMSO-d6) 7.61 (s,1H), 7.37 (q, J=7.6 Hz, 1H), 7.16 (s, 1H), 7.09 (t, J=8.6 Hz, 1H),7.03-6.94 (m, 2H), 6.00 (brs, 2H), 3.90-3.90 (m, 2H), 3.62-3.45 (m, 2H),1.75 (brs, 1H), 1.39-1.36 (m, 4H), 1.09 (s, 3H). LC/MS (M+1): 345.2.

Compound 5:6-amino-2-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl]-5-(2,3-dichlorophenyl)pyrimidine-4-carboxamide

The title compound was obtained following procedure described above butstarting from ((3S,4S)-3-Methyl-2-oxa-8-aza-spiro[4.5]dec-4-yl)-carbamicacid tert-butyl ester (WUXI, 130 mg, 0.5 mmol) and6-Amino-5-(2,3-dichloro-phenyl)-2-methanesulfonyl-pyrimidine-4-carbonitrile(Intermediate 5, 110 mg, 0.3 mmol) as a white powder (30 mg, 20%, 3steps). 1H NMR (400 MHz, DMSO-d6) 7.71 (s, 1H), 7.51 (dd, J=8.0, 1.5 Hz,1H), 7.28 (t, J=7.8 Hz, 1H), 7.15 (s, 1H), 7.10 (dd, J=7.6, 1.5 Hz, 1H),6.08 (s, 2H), 4.12 (m, 3H), 3.68 (d, J=8.4 Hz, 1H), 3.49 (d, J=8.4 Hz,1H), 3.47-3.32 (m, 2H), 2.89 (d, J=5.2 Hz, 1H), 1.75-1.63 (m, 1H),1.63-1.52 (m, 1H), 1.52-1.38 (m, 2H), 1.38-1.20 (m, 2H), 1.08 (d, J=6.4Hz, 3H). LC/MS (M+1): 451.1.

Compound 6:6-amino-2-{9-amino-3-azabicyclo[3.3.1]nonan-3-yl}-5-(2,3-dichlorophenyl)pyrimidine-4-carboxamide

The title compound was obtained following procedure described above butstarting from tert-butyl N-(3-azabicyclo[3.3.1]nonan-9-yl)carbamate(Achemblock) and6-Amino-5-(2,3-dichloro-phenyl)-2-methanesulfonyl-pyrimidine-4-carbonitrile(Intermediate 4) as a white powder (mixture of isomers—1:1). LC/MS(M+1): 421.3.

Compound 7:6-amino-2-[(1R)-1-amino-8-azaspiro[4.5]decan-8-yl]-5-(2,3-dichlorophenyl)pyrimidine-4-carboxamide

The title compound was obtained following procedure described above butstarting from (R)-(8-Aza-spiro[4.5]dec-1-yl)-carbamic acid tert-butylester (WUXI) and6-Amino-5-(2,3-dichloro-phenyl)-2-methanesulfonyl-pyrimidine-4-carbonitrile(Intermediate 4) as a white powder. 1H NMR (400 MHz, DMSO-d6) 7.50 (dd,J=8.1, 1.6 Hz, 1H), 7.28 (t, J=7.9 Hz, 1H), 7.09 (dd, J=7.6, 1.5 Hz,1H), 4.44 (t, J=12.2 Hz, 2H), 3.00 (q, J=10.4 Hz, 2H), 2.65 (t, J=7.3Hz, 1H), 1.91-1.71 (m, 2H), 1.69-1.56 (m, 1H), 1.56-1.42 (m, 3H),1.42-1.25 (m, 2H), 1.25-1.08 (m, 2H). LC/MS (M+1): 435.1.

Compound 8:6-amino-2-[(1R)-1-amino-3,3-difluoro-8-azaspiro[4.5]decan-8-yl]-5-(2,3-dichlorophenyl)pyrimidine-4-carboxamide

The title compound was obtained following procedure described above butstarting from ((R)-3,3-Difluoro-8-aza-spiro[4.5]dec-1-yl)-carbamic acidtert-butyl ester (WUXI) and6-Amino-5-(2,3-dichloro-phenyl)-2-methanesulfonyl-pyrimidine-4-carbonitrile(Intermediate 4) as a white powder. 1H NMR (400 MHz, DMSO-d6) δ 7.72 (s,1H), 7.51 (dd, J=8.0, 1.5 Hz, 1H), 7.28 (t, J=7.8 Hz, 1H), 7.20-7.13 (m,1H), 7.10 (dt, J=7.6, 1.4 Hz, 1H), 6.09 (s, 2H), 4.54 (t, J=16.4 Hz,2H), 3.13-2.84 (m, 3H), 2.47-2.28 (m, 2H), 2.14-1.85 (m, 2H), 1.74-1.43(m, 4H), 1.30 (dd, J=27.6, 13.3 Hz, 2H). LC/MS (M+1): 471.1.

Compound 9:6-Amino-2-(4-amino-4-methyl-piperidin-1-yl)-5-(2,3-dichloro-phenyl)-pyrimidine-4-carboxylicacid methylamide

A solution of6-amino-2-(4-amino-4-methylpiperidin-1-yl)-5-(2,3-dichlorophenyl)-pyrimidine-4-carboxylicacid (Intermediate 6, 110 mg, 0.27 mmol) and SO₂Cl₂ (0.5 mL) in MeOH (5mL) was heated at 80° C. for 4 h under nitrogen atmosphere. Solvent wasremoved under reduced pressure and the residue was redissolved in a 2Mmethyl amine solution in THF (2 mL) and heated at 90° C. for 16 h in asealed reactor. Solvent was removed under reduced pressure and the crudewas purified by preparative HPLC (XBridge Shield RP18 OBD Column, 5μm,19*150 mm; Water (10 mM NH₄HCO₃): ACN gradient from 38% to 68% in 8min) to afford the title compound as a white solid (12 mg, 24%). mp:147-149° C.; δ 1H NMR (300 MHz, DMSO-d6) 8.32 (d, J=5.0 Hz, 1H), 7.49(dd, J=8.1, 1.5 Hz, 1H), 7.26 (t, J=7.9 Hz, 1H), 7.05 (dd, J=7.6, 1.6Hz, 1H), 6.07 (s, 2H), 4.02-3.92 (m, 2H), 3.64-3.53 (m, 2H), 2.71 (d,J=1.5 Hz, 3H), 1.44-1.39 (m, 6H), 1.07 (s, 3H). LC/MS (M+1): 409.1.

Compound 10:6-amino-2-[6-amino-7-hydroxy-1-(propan-2-yl)-2-azaspiro[3.4]octan-2-yl]-5-(2,3-dichlorophenyl)pyrimidine-4-carboxamide

The title compound was obtained following procedure described above butstarting from rac-tert-butyln-[(6r,7r)-7-hydroxy-1-(propan-2-yl)-2-azaspiro[3.4]octan-6-yl]carbamatehydrochloride (Enamine) and6-Amino-5-(2,3-dichloro-phenyl)-2-methanesulfonyl-pyrimidine-4-carbonitrile(Intermediate 4) as a white powder (mixture of two diastereoisomers).LC/MS (M+1): 465.2.

Compound 11:6-amino-2-[8-(aminomethyl)-6-azaspiro[3.4]octan-6-yl]-5-(2,3-dichlorophenyl)pyrimidine-4-carboxamide

The title compound was obtained following procedure described above butstarting from tert-butyl n-((6-azaspiro[3.4]octan-8-yl)methyl)carbamate(Enamine) and6-Amino-5-(2,3-dichloro-phenyl)-2-methanesulfonyl-pyrimidine-4-carbonitrile(Intermediate 4) as a white powder (mixture of isomers). 1H NMR (400MHz, DMSO-d6) δ 7.70 (s, 1H), 7.54-7.47 (m, 1H), 7.32-7.23 (m, 1H), 7.17(s, 1H), 7.13-7.05 (m, 1H), 6.03 (s, 2H), 3.76-3.38 (m, 4H), 2.84 (d,J=12.0 Hz, 1H), 2.41-2.29 (m, 1H), 2.28-1.64 (m, 7H). LC/MS (M+1):421.2.

Compound 12:6-amino-2-[3-(aminomethyl)-8-azabicyclo[3.2.1]octan-8-yl]-5-(2,3-dichlorophenyl)pyrimidine-4-carboxamide

The title compound was obtained following procedure described above butstarting from tert-butyln-((8-azabicyclo[3.2.1]octan-3-yl)methyl)carbamate (Enamine) and6-Amino-5-(2,3-dichloro-phenyl)-2-methanesulfonyl-pyrimidine-4-carbonitrile(Intermediate 4) as a white powder. 1H NMR (400 MHz, Methanol-d4) δ 7.49(dd, J=8.0, 1.6 Hz, 1H), 7.29 (t, J=7.8 Hz, 1H), 7.16 (dd, J=7.6, 1.6Hz, 1H), 4.80-4.74 (m, 2H), 2.48 (d, J=6.7 Hz, 2H), 2.15-1.95 (m, 3H),1.84 (d, J=7.5 Hz, 2H), 1.73-1.62 (m, 2H), 1.48 (td, J=13.5, 2.9 Hz,2H). LC/MS (M+1): 421.2.

Compounds 13 and 14:6-amino-5-(2,3-dichlorophenyl)-2-[(1R,7S,11s)-11-amino-9-azabicyclo[5.3.1]undecan-9-yl]pyrimidine-4-carboxamideand6-amino-5-(2,3-dichlorophenyl)-2-[(1R,7S,11r)-11-amino-9-azabicyclo[5.3.1]undecan-9-yl]pyrimidine-4-carboxamide

The title compounds were obtained following procedure described abovebut starting from tert-butyln-(9-azabicyclo[5.3.1]undecan-11-yl)carbamate oxalic acid (Enamine) and6-Amino-5-(2,3-dichloro-phenyl)-2-methanesulfonyl-pyrimidine-4-carbonitrile(Intermediate 4) as a mixture of two diastereoisomers. The two isomerswere separated by preparative-HPLC (XBridge Prep C-18 OBD 10 uM, 30×250.30-80% ACN/Water/(0.1% Ammonium Hydroxide)/ACN gradient from 30% to 80%in 15 min).

First eluting isomer (arbitrarily assigned):6-amino-5-(2,3-dichlorophenyl)-2-[(1R,7S,11s)-11-amino-9-azabicyclo[5.3.1]undecan-9-yl]pyrimidine-4-carboxamide;white powder (8.2 mg, 17%), 1H NMR (400 MHz, DMSO-d6) 7.66 (s, 1H), 7.51(dd, J=8.0, 1.5 Hz, 1H), 7.28 (t, J=7.8 Hz, 1H), 7.23-7.08 (m, 2H), 6.10(s, 2H), 4.81 (dd, J=13.3, 6.3 Hz, 2H), 3.09 (t, J=6.0 Hz, 1H), 2.85(dd, J=13.5, 4.5 Hz, 2H), 2.02 (d, J=3.1 Hz, 1H), 1.95-1.73 (m, 3H),1.73-1.56 (m, 3H), 1.51 (dt, J=14.9, 7.5 Hz, 2H), 1.29 (q, J=12.9, 12.5Hz, 2H), 1.19-1.00 (m, 1H). LC/MS (M+1): 449.5.

Second eluting isomer (arbitrarily assigned):6-amino-5-(2,3-dichlorophenyl)-2-[(1R,7S,11r)-11-amino-9-azabicyclo[5.3.1]undecan-9-yl]pyrimidine-4-carboxamide,white powder (4.7 mg, 10%), 1H NMR (400 MHz, Methanol-d4) 7.48 (dd,J=8.0, 1.6 Hz, 1H), 7.29 (t, J=7.8 Hz, 1H), 7.17 (dd, J=7.6, 1.6 Hz,1H), 4.59-4.52 (m, 2H), 3.47-3.42 (m, 1H), 3.28-3.24 (m, 1H), 2.01-1.90(m, 2H), 1.88-1.71 (m, 4H), 1.61-1.39 (m, 4H), 1.37-1.19 (m, 2H). LC/MS:449.2.

Compound 15:2-(4-amino-4-methylpiperidin-1-yl)-5-(2,3-dichlorophenyl)-6-hydroxypyrimidine-4-carboxamideStep 1: tert-butylN-{1-[4-amino-6-carbamoyl-5-(2,3-dichlorophenyl)pyrimidin-2-yl]-4-methylpiperidin-4-yl}carbamate

A solution of tert-butylN-[1-[4-amino-6-cyano-5-(2,3-dichlorophenyl)pyrimidin-2-yl]-4-methylpiperidin-4-yl]carbamate(intermediate 5, 371 mg, 0.78 mmol) in EtOH (5 mL) and aq. NaOH (0.8 mLof a 2.2 M solution) was heated at 100° C. for 16 h. The reactionmixture was cooled down to RT and pH was adjusted 7 by addition of a 3MHCl solution. The resulting solution was extracted with EtOAc (30 mL)and combined organic layers were washed with brine, dried over sodiumsulfate, filtered and concentrated. Purification by flash chromatographyon silica (EtOAc: MeOH, gradient from 100:0 to 80:20) afforded the titlecompound as an off-white solid (180 mg, 49%). LC/MS: 495.1.

Step 2:2-(4-amino-4-methylpiperidin-1-yl)-5-(2,3-dichlorophenyl)-6-hydroxypyrimidine-4-carboxamide

A solution of tert-butylN-[1-[4-amino-6-carbamoyl-5-(2,3-dichlorophenyl)pyrimidin-2-yl]-4-methylpiperidin-4-yl]carbamate(60 mg, 0.122 mmol) and NaNO₂ (88 mg, 1.3 mmol) in THE (5 mL), water (3mL) and conc. HCl (1 mL) was stirred at 0° C. for 4 h. The solvent wasremoved under reduced pressure and the residue was diluted with aq HCl(5 M, 2 mL) and stirred at room temperature for 30 min. It was thenpoured onto ice and extracted with EtOAc (3×30 mL). Combined organiclayers were washed with brine, dried over magnesium sulfate, filteredand concentrated. Purification by preparative HPLC (XBridge OBD C18Column, 19*250 mm,5 um; Water (10 mM NH₄HCO₃) and ACN, gradient from 58%to 80% in 8 min) to give the title compound as a yellow solid (4 mg,8%). 1H NMR (400 MHz, Methanol-d4) 7.48-7.47 (m, 1H), 7.45-7.44 (m, 1H),7.28-7.23 (m, 1H), 4.41-4.20 (m, 2H), 3.51-3.38 (m, 2H), 1.92-1.81 (m,4H), 1.54-1.50 (m, 3H),. LC/MS (M+1): 396.1.

Compound 16:2-(4-Amino-4-methyl-piperidin-1-yl)-6-chloro-5-(2,3-dichloro-phenyl)-pyrimidine-4-carboxylicacid amide

A solution of NaNO₂ (197 mg, 2.7 mmol) in water (1 mL) was added to asolution of tert-butylN-[1-[4-amino-6-cyano-5-(2,3-dichlorophenyl)pyrimidin-2-yl]-4-methylpiperidin-4-yl]carbamate(intermediate 5, 440 mg, 0.90 mmol) in aq. HCl (6M solution, 5 mL, 29.6mmol) maintained at 0° C. The reaction mixture was stirred at 0° C. for30 min, then at room temperature for 4 h. The reaction mixture waspoured into ice and pH was adjusted to 9 by addition of aq. NaOH (2M).It was extracted with EtOAc (3×30 mL). Combined organic layers werewashed with brine, dried over magnesium sulfate, filtered andconcentrated. Purification by flash chromatography on silica (PE:EtOAc,50:50) afforded a yellow solid (210 mg) which was redissolved in ACN (4mL) and aq. NaOH (0.5 M, 4 mL). The reaction mixture was heated at 70°C. for 1 h. It was then diluted with water (15 mL) and extracted withEtOAc (3×30 mL). Combined organic layers were dried over magnesiumsulfate, filtered and concentrated. Purification by flash chromatography(PE:EtOAc, 50:50) afforded the title compound as a yellow solid (80 mg,51%). 1H NMR (400 MHz, Methanol-d4) 7.53 (dd, J=8.0, 1.6 Hz, 1H), 7.30(t, J=7.9 Hz, 1H), 7.17 (dd, J=7.6, 1.6 Hz, 1H), 4.09-4.01 (m, 2H), 3.89(d, J=5.5 Hz, 2H), 1.65 (qdd, J=13.2, 7.5, 4.3 Hz, 4H), 1.27 (s, 3H).LC/MS (M+1): 415.0.

Compound 17:6-Amino-2-(4-amino-4-methyl-piperidin-1-yl)-5-(2,3-dichloro-phenyl)-pyrimidine-4-carboxylicacid (2-hydroxy-ethyl)-amide

The title compound was obtained following procedure described above butstarting from6-amino-2-(4-[[(tert-butoxy)carbonyl]amino]-4-methylpiperidin-1-yl)-5-(2,3-dichlorophenyl)pyrimidine-4-carboxylicacid (intermediate 7) and 2-aminoethan-1-ol as a white solid. mp:125-127° C. 1H NMR (400 MHz, Methanol-d4) 7.54-7.47 (m, 1H), 7.31 (t,J=7.8 Hz, 1H), 7.18-7.12 (m, 1H), 4.08-3.97 (m, 2H), 3.82-3.71 (m, 2H),3.62-3.55 (m, 2H), 3.30 (d, J=5.6 Hz, 2H), 1.68-1.53 (m, 3H), 1.25 (s,3H). LC/MS (M+1): 439.2.

Compound 18:2-(4-Amino-4-methyl-piperidin-1-yl)-5-(2,3-dichloro-phenyl)-6-methyl-pyrimidine-4-carboxylicacid amide Step 1: tert-butylN-{1-[4-cyano-5-(2,3-dichlorophenyl)-6-methylpyrimidin-2-yl]-4-methylpiperidin-4-yl}carbamate

A mixture of tert-butylN-[1-(5-bromo-4-cyano-6-methylpyrimidin-2-yl)-4-methylpiperidin-4-yl]carbamate(Intermediate 8, 2.3 g, 5.5 mmol), (2,3-dichlorophenyl)boronic acid (2.2g, 11 mmol), Pd(PPh₃)₄(1.34 g, 1.1 mmol) and NaHCO₃ (2.43 g, 27.4 mmol)in dioxane (9 mL) and water (3 mL) was heated at 110° C. for 2 h undernitrogen atmosphere in a sealed reactor. The solvent was removed underreduced pressure and the crude was purified by flash chromatography onsilica (PE:EtOAc, gradient from 100:0 to 50:50) to afford the titlecompound as a yellow solid (3 g, 100%). LC/MS (M+1): 476.4.

Step 2:2-(4-Amino-4-methyl-piperidin-1-yl)-5-(2,3-dichloro-phenyl)-6-methyl-pyrimidine-4-carboxylicacid amide

A solution of tert-butylN-[1-[4-cyano-5-(2,3-dichlorophenyl)-6-methylpyrimidin-2-yl]-4-methylpiperidin-4-yl]carbamate(100 mg, 0.199 mmol) in conc. HCl (3 mL) was stirred at room temperatureunder nitrogen atmosphere for 16 h. The crude mixture was directlypurified by preparative HPLC (XBridge Prep OBD C18 Column, 30*150 mm 5um; Water (10 mM NH₄HCO₃) and ACN gradient from 32% to 62% in 8 min).The title compound was isolated as a yellow solid (25 mg, 31%). mp:103-105° C. 1H NMR (400 MHz, Methanol-d4) 9.38 (s, 1H), 8.07 (d, J=1.5Hz, 1H), 7.77 (d, J=3.1 Hz, 1H), 7.72 (d, J=3.1 Hz, 1H), 7.64 (d, J=1.8Hz, 1H), 4.46 (d, J=12.7 Hz, 2H), 3.67 (s, 2H), 2.03 (d, J=13.7 Hz, 4H),1.58 (s, 3H). LC/MS (M+1): 394.1.

Compound 30 and 31:(4M)-2-(4-amino-4-methylpiperidin-1-yl)-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carboxamideand(4P)-2-(4-amino-4-methylpiperidin-1-yl)-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carboxamide

A mixture of atropisomers from compound 18 (250 mg) was separated bypreparative HPLC (Column: CHIRALPAK IG, 2×25 cm, 5 um, Hexane+ 8 mmol/LNH3·MeOH: EtOH-50%).

First eluting isomer (compound 30): white solid, 60 mg, RT=6.96 min, 1HNMR (300 MHz, DMSO-d6): 7.91.(s, 1H), 7.56 (dd, J=8.0, 1.6 Hz, 1H),7.40-7.28 (m, 2H), 7.18 (dd, J=7.6, 1.6 Hz, 1H), 4.01 (d, J=13.7 Hz,2H), 3.70 (dt, J=12.8, 6.3 Hz, 2H), 1.98 (s, 4H), 1.42 (d, J=5.4 Hz,4H), 1.10 (s, 3H); LC/MS (M+1): 394.1, mp: 160-162° C.

Second eluting isomer (compound 31): white solid, 40 mg, RT=14.5 min, 1HNMR (300 MHz, DMSO-d6): 7.91 (s, 1H), 7.56 (dd, J=8.0, 1.6 Hz, 1H),7.40-7.29 (m, 2H), 7.18 (dd, J=7.6, 1.6 Hz, 1H), 4.03 (d, J=13.4 Hz,2H), 3.68 (dt, J=13.1, 6.4 Hz, 2H), 1.98 (s, 3H), 1.78 (d, J=9.2 Hz,2H), 1.41 (d, J=5.3 Hz, 4H), 1.09 (s, 4H). LC/MS (M+1): 394.1, mp:190-192° C.

Compound 19:2-(4-Amino-4-methyl-piperidin-1-yl)-6-chloro-5-(3-fluoro-phenyl)-pyrimidine-4-carboxylicacid amide Step 1: tert-butylN-{1-[4-amino-6-carbamoyl-5-(3-fluorophenyl)pyrimidin-2-yl]-4-methylpiperidin-4-yl}carbamate

The title compound was obtained following procedure described forcompound 2 but starting from tert-butylN-[1-(4-amino-5-bromo-6-carbamoylpyrimidin-2-yl)-4-methylpiperidin-4-yl]carbamate(Intermediate 2) and (3-fluorophenyl)boronic acid as a brown solid.LC/MS (M+1): 445.2.

Step2:2-(4-Amino-4-methyl-piperidin-1-yl)-6-chloro-5-(3-fluoro-phenyl)-pyrimidine-4-carboxylicacid amide

The title compound was obtained following a procedure similar to the onedescribed for compound 16 but starting from tert-butylN-[1-[4-amino-6-carbamoyl-5-(3-fluorophenyl)pyrimidin-2-yl]-4-methylpiperidin-4-yl]carbamate.The title compound was isolated as a white solid. mp: 110-112° C.1H NMR(400 MHz, Methanol-d4) 7.53-7.39 (m, 1H), 7.42-7.36 (m, 1H), 7.16-6.99(m, 5H), 4.55-4.45 (m, 3H), 3.54 (ddd, J=14.1, 9.7, 3.9 Hz, 3H), 2.05(s, 1H), 2.00-1.87 (m, 1H), 1.85 (ddd, J=18.0, 8.3, 3.8 Hz, 5H), 1.54(s, 4H). LC/MS (M+1): 364.0.

Compound 20:6-Amino-2-(4-amino-4-methyl-piperidin-1-yl)-5-(2,3-dichloro-phenyl)-pyrimidine-4-carboxylicacid hydroxyamide Step 1: methyl6-amino-2-(4-amino-4-methylpiperidin-1-yl)-5-(2,3-dichlorophenyl)pyrimidine-4-carboxylate

A solution of6-amino-2-(4-[[(tert-butoxy)carbonyl]amino]-4-methylpiperidin-1-yl)-5-(2,3-dichlorophenyl)pyrimidine-4-carboxylicacid (Intermediate 7, 40 mg, 0.073 mmol) and SOCl₂ (1 mL, 13.1 mmol) inMeOH (4 mL) was stirred at 70° C. for 2 h. Solvent was then removedunder reduced pressure to afford the title compound as a brown solid (38mg, 96%). LC/MS (M+1): 410.2.

Step 2:6-Amino-2-(4-amino-4-methyl-piperidin-1-yl)-5-(2,3-dichloro-phenyl)-pyrimidine-4-carboxylicacid hydroxyamide

A solution of methyl6-amino-2-(4-amino-4-methylpiperidin-1-yl)-5-(2,3-dichlorophenyl)pyrimidine-4-carboxylate(33 mg, 0.1 mmol), NH₂OH (20 μl, 50% in water) in MeOH (1 mL) wasstirred at room temperature for 16 h. The solvent was removed underreduced pressure and the crude was purified by preparative HPLC (XBridgeShield RP18 OBD Column, 5 um,19*150 mm; Water (10 mM NH₄HCO₃) and ACNgradient from 25% to 55% in 8 min) to give the title compound as a whitesolid (9 mg, 33%). 1H NMR (400 MHz, DMSO-d6) 7.56-7.49 (m, 2H), 7.29 (t,J=7.9 Hz, 2H), 7.12 (s, 1H), 7.12 (d, J=7.8 Hz, 1H), 6.10 (s, 4H), 3.91(d, J=12.6 Hz, 4H), 3.64 (s, 5H), 1.39 (d, J=9.5 Hz, 10H), 1.24 (s, 1H),1.09 (s, 6H). LC/MS (M+1): 411.1.

Compound 21:6-Amino-2-(4-amino-4-methyl-piperidin-1-yl)-5-(2,3-dichloro-phenyl)-pyrimidine-4-carboxylicacid hydrazide Step 1: tert-butylN-{1-[4-amino-5-(2,3-dichlorophenyl)-6-(hydrazinecarbonyl)-pyrimidin-2-yl]-4-methylpiperidin-4-yl}carbamate

A solution of6-amino-2-(4-{[(tert-butoxy)carbonyl]amino}-4-methylpiperidin-1-yl)-5-(2,3-dichlorophenyl)pyrimidine-4-carboxylicacid (intermediate 7, 50 mg, 0.084 mmol), HATU (50 mg, 0.126 mmol), DIEA(34 mg, 0.25 mmol) and hydrazine (6 ul) in DMF (5.0 mL) was stirred at80° C. for 24 h. The reaction mixture was then diluted with water/ice(25 mL) and extracted with EtOAc (3×30 mL). Combined organic layers werewashed with brine, dried over magnesium sulfate, filtered andconcentrated. Purification by flash chromatography on silica (PE:EtOAc,90:10) afforded the title compound as a yellow solid (40 mg, 88%).

Step 2:6-Amino-2-(4-amino-4-methyl-piperidin-1-yl)-5-(2,3-dichloro-phenyl)-pyrimidine-4-carboxylicacid hydrazide

A solution of tert-butylN-[1-[4-amino-5-(2,3-dichlorophenyl)-6-(hydrazinecarbonyl)-pyrimidin-2-yl]-4-methylpiperidin-4-yl]carbamate(40 mg, 0.074 mmol) in HCl (2 mL of a 4N solution in dioxane) wasstirred at room temperature for 4 h. The solvent was then removed underreduced pressure and the crude was purified by preparative HPLC (XBridgePrep OBD C18 Column, 30×150 mm 5 um; Water (10 mM NH₄HCO₃) and ACNgradient from 30% to 60% in 8 min). The title compound was isolated as awhite solid (4.3 mg,13%). mp: 171-173° C. 1H NMR (300 MHz, Methanol-d4)7.50 (d, J=7.8 Hz, 1H), 7.30 (t, J=7.8 Hz, 1H), 7.15 (d, J=7.5 Hz, 1H),4.05 (dt, J=13.9, 5.2 Hz, 2H), 3.69 (ddd, J=13.1, 7.7, 4.3 Hz, 2H),1.69-1.50 (m, 4H), 1.26 (s, 3H). LC/MS (M+1): 410.1.

Compound 22:2-(4-Amino-4-methyl-piperidin-1-yl)-6-fluoro-5-(3-fluoro-phenyl)-pyrimidine-4-carboxylicacid amide

A mixture of tert-butylN-[1-[4-amino-6-carbamoyl-5-(3-fluorophenyl)pyrimidin-2-yl]-4-methylpiperidin-4-yl]carbamate(prepared in step 1 from compound 4, 179 mg, 0.396 mmol), phenylboronicacid (3.0 mL), NaNO₂ (139 mg, 1.9 mmol) and KF (117 mg, 1.9 mmol) wasstirred for 1 h at 0° C. The reaction was then quenched by addition ofaq. NH₄Cl (10 mL) and extracted with EtOAc (3×30 mL). Combined organiclayers were washed with brine, dried over magnesium sulfate, filteredand concentrated. The crude product (50 mg) was purified by preparativeHPLC (XBridge Prep OBD C18 Column, 19×250 mm,5 um; Water (10 mM NH₄HCOs)and ACN, gradient from 30% to 45% in 8 min) to afford the title compoundas a white solid (8 mg, 5%). mp: 90-92° C. 1H NMR (400 MHz, Methanol-d4)7.45-7.35 (m, 1H), 7.17-7.05 (m, 3H), 4.03 (s, 2H), 3.85 (s, 2H),1.72-1.55 (m, 4H), 1.28 (s, 3H). LC/MS (M+1): 348.1.

Compound 23:6-amino-2-[4-(aminomethyl)-8-oxa-2-azaspiro[4.5]decan-2-yl]-5-(2,3-dichlorophenyl)pyrimidine-4-carboxamide

The title compound was obtained following procedure described above butstarting from6-Amino-5-(2,3-dichloro-phenyl)-2-methanesulfonyl-pyrimidine-4-carbonitrile(intermediate 4) and tert-butyln-((8-oxa-2-azaspiro[4.5]decan-4-yl)methyl)carbamate (enamine) as awhite powder. 1H NMR (400 MHz, DMSO-d6) 7.78 (s, 1H), 7.51 (dd, J=8.1,1.6 Hz, 1H), 7.28 (t, J=7.8 Hz, 1H), 7.18 (s, 1H), 7.10 (dt, J=7.6, 1.5Hz, 1H), 6.04 (s, 2H), 3.84-3.64 (m, 4H), 2.72-2.61 (m, 2H), 1.98-1.84(m, 2H), 1.77 (dd, J=18.1, 6.4 Hz, 2H), 1.55 (t, J=10.6 Hz, 2H), 1.36(t, J=16.2 Hz, 3H). LC/MS (M+1): 451.3

Compound 24:2-[3a-(aminomethyl)-octahydro-1H-isoindol-2-yl]-6-amino-5-(2,3-dichlorophenyl)pyrimidine-4-carboxamide

The title compound was obtained following procedure described above butstarting from6-Amino-5-(2,3-dichloro-phenyl)-2-methanesulfonyl-pyrimidine-4-carbonitrile(intermediate 4) and tert-butyln-(octahydro-1h-isoindol-3a-ylmethyl)-carbamate (Enamine) as a whitepowder (mixture of isomers). 1 H NMR (400 MHz, DMSO-d6) 7.68 (s, 1H),7.51 (dd, J=8.1, 1.6 Hz, 1H), 7.28 (t, J=7.8 Hz, 1H), 7.16 (s, 1H),7.13-7.07 (m, 1H), 6.00 (s, 2H), 3.71-3.35 (m, 4H), 2.64 (s, 1H),2.10-1.99 (m, 1H), 1.66-1.22 (m, 9H). LC/MS (M+1): 435.

Compound 25:2-(4-amino-4-methylpiperidin-1-yl)-5-(3-fluorophenyl)-6-hydroxypyrimidine-4-carboxamidehydrochloride

A solution of2-(4-amino-4-methylpiperidin-1-yl)-6-fluoro-5-(3-fluorophenyl)-pyrimidine-4-carboxamide(example 36, 50 mg, 0.072 mmol) in conc. HCl (1.0 mL) and water (2.0 mL)was stirred at 50° C. for 2 h. The resulting mixture was concentratedunder reduced pressure and directly purified by preparative HPLC(XBridge Prep OBD C18 Column, 19*250 mm,5 um; Water (10 mM NH₄HCO₃ andACN (gradient from 58% to 80% in 8 min) to give the title compound as awhite solid (8.6 mg, 31%). 1H NMR (400 MHz, DMSO-d6) 7.63 (s, 1H),7.33-7.23 (m, 2H), 7.12-7.02 (m, 2H), 7.04-6.96 (m, 1H), 4.06 (s, 1H),3.81 (s, 2H), 3.61 (s, 2H), 1.48 (s, 4H), 1.17 (s, 3H). LC/MS (M+1):346.1

Compounds 66 and 67:(5P)-6-amino-2-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl]-5-(2,3-dichlorophenyl)pyrimidine-4-carboxamideand(5M)-6-amino-2-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl]-5-(2,3-dichlorophenyl)pyrimidine-4-carboxamideStep 1: tert-butylN-[(3S,4S)-8-[4-amino-6-cyano-5-(2,3-dichlorophenyl)pyrimidin-2-yl]-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-yl]carbamate

A solution of6-Amino-5-(2,3-dichloro-phenyl)-2-methanesulfonyl-pyrimidine-4-carbonitrile(Intermediate 4, 1.50 g; 4.37 mmol), tert-butylN-[(3S,4S)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-yl]carbamate (WUXI;1.77g; 6.56 mmol) DIEA (2.27 mL) in anhydrous DMSO (60 mL) was stirred for 6h at 70° C. The reaction mixture was then diluted with water (300 mL)and EtOAc (800 mL). Organic layer was washed with water (2×300 mL) andbrine (300 mL), dried over sodium sulfate, filtered and concentrated.Purification by flash chromatography on silica (hexane:EtOAc, gradientfrom 95:5 t 20:80) afforded the title compound as a white solid (2.07 g,89%). 1H NMR (400 MHz, DMSO-d6): 7.72 (dd, J=8.0, 1.6 Hz, 1H), 7.45 (t,J=7.8 Hz, 1H), 7.39 (dd, J=7.7, 1.7 Hz, 1H), 6.97 (d, J=10.5 Hz, 1H),4.17 (p, J=6.2 Hz, 1H), 3.89 (dd, J=10.6, 5.1 Hz, 1H), 3.86-3.75 (m,1H), 3.75-3.61 (m, 3H), 3.57-3.43 (m, 2H), 1.68-1.50 (m, 3H), 1.50-1.31(m, 10H), 1.03 (d, J=6.3 Hz, 3H); LC/MS (M+1): 533.1

Step 2: tert-butylN-[(3S,4S)-8-[4-amino-6-carbamoyl-5-(2,3-dichlorophenyl)pyrimidin-2-yl]-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-yl]carbamate

A solution of tert-butylN-[(3S,4S)-8-[4-amino-6-cyano-5-(2,3-dichlorophenyl)pyrimidin-2-yl]-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-yl]carbamate(Intermediate 4; 2.0 g; 3.75 mmol), potassium carbonate (2.59 g; 18.75mmol) and hydrogen peroxide, 30% weight (7.65 ml; 67.49 mmol) in DMSO(50 mL) was stirred at 50° C. for 4.5 h. The reaction mixture wasdiluted with EtOAc (800 mL) and washed with a solution of sodiumthiosulfate pentahydrate (50.25 g; 202.46 mmol) in water (500 mL). Theorganic layer was washed with water (2×400 mL) and brine (400 mL), driedover sodium sulfate, filtered and concentrated to give the titlecompound as a white solid (2.2 g, 95.8%). 1H NMR (Bruker 400 MHz,DMSO-d6): 7.73 (s, 1H), 7.51 (dd, J=8.0, 1.5 Hz, 1H), 7.28 (t, J=7.8 Hz,1H), 7.14 (s, 1H), 7.10 (dd, J=7.4, 1.2 Hz, 1H), 6.97 (d, J=10.5 Hz,1H), 6.08 (s, 2H), 4.22-4.11 (m, 1H), 3.96-3.78 (m, 2H), 3.78-3.64 (m,3H), 3.61-3.47 (m, 2H), 1.69-1.50 (m, 4H), 1.40 (s, 9H), 1.03 (d, J=6.3Hz, 3H). LC/MS (M+1): 551.2.

Step 3:(5P)-6-amino-2-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl]-5-(2,3-dichlorophenyl)pyrimidine-4-carboxamideand(5M)-6-amino-2-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl]-5-(2,3-dichlorophenyl)pyrimidine-4-carboxamide

A solution of tert-butylN-[(3S,4S)-8-[4-amino-6-carbamoyl-5-(2,3-dichlorophenyl)pyrimidin-2-yl]-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-yl]carbamate(2.20 g; 3.59 mmol; 1.00 eq.) in Dichloromethane (44 mL) and TFA (22 mL)was stirred for 1 hour at room temperature. Toluene was added and themixture was concentrated under reduced pressure. This operation wasrepeated twice. The crude residue (3.3 g) was purified by preparativeSFC (column Amylose2, 250×21 mm, 5 micron, Methanol+20 mM NH₄OH: CO₂;45-55).

First elutinq fraction (compound 67)(5M)-6-amino-2-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl]-5-(2,3-dichlorophenyl)pyrimidine-4-carboxamide:white amorphous solid; 637 mg (40%). RT=4.04 min; ed=100%; 1H NMR (400MHz, DMSO-d6): 7.71 (s, 1H), 7.51 (dd, J=8.1, 1.5 Hz, 1H), 7.28 (t,J=7.8 Hz, 1H), 7.15 (s, 1H), 7.10 (dd, J=7.6, 1.5 Hz, 1H), 6.08 (s, 2H),4.16-3.99 (m, 3H), 3.68 (d, J=8.4 Hz, 1H), 3.50 (d, J=8.4 Hz, 1H),3.48-3.25 (m, 4H), 2.91 (d, J=5.1 Hz, 1H), 1.77-1.34 (m, 6H), 1.09 (d,J=6.4 Hz, 3H); LC/MS (M+1): 451.0.

Second elutinq fraction (compound 66)(5P)-6-amino-2-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl]-5-(2,3-dichlorophenyl)pyrimidine-4-carboxamide:white solid; 603 mg (37%). RT=4.53 min; ed=95%; 1H NMR (Bruker 400 MHz,DMSO-d6): 7.72 (s, 1H), 7.51 (dd, J=8.0, 1.6 Hz, 1H), 7.28 (t, J=7.8 Hz,1H), 7.15 (s, 1H), 7.10 (dd, J=7.7, 1.6 Hz, 1H), 6.08 (s, 2H), 4.15-3.99(m, 3H), 3.68 (d, J=8.4 Hz, 1H), 3.50 (d, J=8.4 Hz, 1H), 3.48-3.34 (m,4H), 2.90 (d, J=5.2 Hz, 1H), 1.75-1.63 (m, 1H), 1.63-1.53 (m, 1H),1.53-1.29 (m, 4H), 1.08 (d, J=6.4 Hz, 3H). LC/MS (M+1): 451.0.

Compound 85:2-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl]-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carboxamideStep 1: tert-butylN-[(3S,4S)-8-[4-cyano-5-(2,3-dichlorophenyl)-6-methylpyrimidin-2-yl]-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-yl]carbamate

Under an atmosphere on N₂, tert-butylN-[(3S,4S)-8-(5-bromo-4-cyano-6-methylpyrimidin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-yl]carbamate(108 mg; 0.23 mmol) was combined with 2,3-dichlorophenylboronic acid (66mg; 0.35 mmol) and cesium carbonate (151 mg; 0.46 mmol) in 1,4-dioxane(2.2 mL) and water (0.54 mL). The mixture was degassed for 10 min beforethe addition of tetrakis(triphenylphosphine)palladium(0) (53 mg; 0.05mmol) and stirred at 100° C. for 2 h. The reaction mixture was cooled atroom temperature and diluted with EtOAc (10 mL). It was filtered througha celite pad which was rinsed with EtOAc (10 mL). Filtrate wasconcentrated and purified by flash chromatography on silica(hexane:EtOAc, gradient from 95:5 to 20:80) to afford the title compoundas a white solid (72 mg, 58%). 1H NMR (Bruker 400 MHz, DMSO-d6): 7.80(dd, J=6.4, 3.2 Hz, 1H), 7.60-7.47 (m, 2H), 7.01 (d, J=10.5 Hz, 1H),4.18 (p, J=6.2 Hz, 1H), 3.96-3.84 (m, 2H), 3.84-3.73 (m, 2H), 3.70 (d,J=8.5 Hz, 1H), 3.66-3.58 (m, 1H), 3.54 (d, J=8.2 Hz, 1H), 2.12 (s, 3H),1.75-1.44 (m, 4H), 1.40 (s, 9H), 1.03 (d, J=6.3 Hz, 3H). LC/MS (M+1):532.2.

Step 2: tert-butylN-[(3S,4S)-8-[4-carbamoyl-5-(2,3-dichlorophenyl)-6-methylpyrimidin-2-yl]-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-yl]carbamate

A solution of tert-butylN-[(3S,4S)-8-[4-cyano-5-(2,3-dichlorophenyl)-6-methylpyrimidin-2-yl]-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-yl]carbamate(100 mg; 0.19 mmol), potassium carbonate (130 mg; 0.94 mmol) andhydrogen peroxide, 30% weight (0.38 mL; 3.38 mmol) in DMSO (2.5 mL) wasstirred at 50° C. for 6 h. The reaction mixture was diluted with EtOAc(50 mL) and washed with a solution of sodium thiosulfate pentahydrate(2.52 g; 10.1 mmol) in water (25 mL). The organic layer was washed withwater (2×25 mL) and brine (25 mL), dried over sodium sulfate, filteredand concentrated to give the title compound as a white solid (103 mg,94%). LC/MS (M+1): 550.2

Step 3:2-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl]-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carboxamide

A solution of tert-butylN-[(3S,4S)-8-[4-carbamoyl-5-(2,3-dichlorophenyl)-6-methylpyrimidin-2-yl]-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-yl]carbamate(100.00 mg; 0.18 mmol; 1.00 eq.) in dichloromethane (2 mL) and TFA (1mL) was stirred for 1 hour at room temperature. Toluene was added andthe mixture was concentrated under reduced pressure. This operation wasrepeated twice. The crude was then purified by preparative HPLC (XBridgePrep C-18 OBD 10 uM, 30×250; ACN:Water with 0.1% Ammonium Hydroxide,gradient from 20 to 60% in 15 minutes) to afford the title compound as awhite powder (70 mg, 86%). 1H NMR (Bruker 400 MHz, DMSO-d6): 7.93 (s,1H), 7.58 (dd, J=8.0, 1.6 Hz, 1H), 7.43-7.29 (m, 2H), 7.20 (dd, J=7.7,1.6 Hz, 1H), 4.23-4.10 (m, 2H), 4.08 (dd, J=6.5, 5.2 Hz, 1H), 3.70 (d,J=8.4 Hz, 1H), 3.61-3.42 (m, 3H), 2.93 (d, J=5.2 Hz, 1H), 2.00 (s, 3H),1.77 1.68 (m, 1H), 1.68-1.42 (m, 5H), 1.09 (d, J=6.4 Hz, 3H); LC/MS(M+1): 450.1.

Compound 94 and 95:(5P)-2-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl]-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carboxamideand(5M)-2-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl]-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carboxamide

The two atropisomers from compound were separate by preparative SFC(column IA, 250×21 mm, 5 micron, Methanol+20 mM NH₄OH: CO₂, 30-70).

First elutinq isomer (compound 94): white amorphous solid, 24 mg,RT=3.32 min, ed=100%, 1H NMR (Bruker 400 MHz, DMSO-d6): 7.93 (s, 1H),7.58 (dd, J=8.0, 1.5 Hz, 1H), 7.42-7.29 (m, 2H), 7.20 (dd, J=7.6, 1.6Hz, 1H), 4.24-4.02 (m, 3H), 3.70 (d, J=8.4 Hz, 1H), 3.62-3.41 (m, 3H),2.92 (d, J=5.2 Hz, 1H), 2.00 (s, 3H), 1.80-1.33 (m, 6H), 1.09 (d, J=6.4Hz, 3H). LC/MS (M+1): 450.2.

Second elutinq isomer (Compound 95): white solid, 22 mg, RT=3.67 min,ed=100%, 1H NMR (400 MHz, DMSO-d6): 7.93 (s, 1H), 7.58 (dd, J=8.0, 1.6Hz, 1H), 7.41-7.30 (m, 2H), 7.20 (dd, J=7.7, 1.6 Hz, 1H), 4.27-3.99 (m,3H), 3.71 (d, J=8.5 Hz, 1H), 3.65-3.39 (m, 3H), 2.94 (d, J=5.2 Hz, 1H),2.00 (s, 3H), 1.81-1.35 (m, 5H), 1.35-1.17 (m, 1H), 1.09 (d, J=6.4 Hz,3H), LC/MS (M+1): 450.2.

Compound 96 and 97:(5M)-2-[(1R)-1-amino-3,3-difluoro-8-azaspiro[4.5]decan-8-yl]-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carboxamideand(5P)-2-[(1R)-1-amino-3,3-difluoro-8-azaspiro[4.5]decan-8-yl]-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carboxamide

The title compounds were obtained following procedure described forcompound 85 but starting from tert-butylN-[(1R)-8-(5-bromo-4-cyano-6-methylpyrimidin-2-yl)-3,3-difluoro-8-azaspiro[4.5]decan-1-yl]carbamate(150.00 mg; 0.31 mmol) and 2,3-dichlorophenylboronic acid (88.28 mg;0.46 mmol) as a white powder (65 mg, 44% for three steps, mixture of thetwo atropisomers).

The two atropisomers were separated by preparative SFC (column Cel4,250×21 mm, 5 micron, Methanol+20 mM NH₄OH: CO2)

First elutinq isomer (compound 96): white solid, 31 mg, RT=, ed=, 1H NMR(Bruker 400 MHz, DMSO-d6): 7.93 (s, 1H), 7.58 (d, J=8.0 Hz, 1H),7.42-7.28 (m, 2H), 7.20 (d, J=7.6 Hz, 1H), 4.61 (dd, J=17.5, 13.3 Hz,2H), 3.18-2.94 (m, 3H), 2.46-2.29 (m, 2H), 2.12-1.91 (m, 5H), 1.78-1.54(m, 4H), 1.36 (dd, J=26.1, 13.4 Hz, 2H), LC/MS (M+1): 470.2.

Second eluting isomer (compound 97): white solid, 25 mg, RT=, ed=, 1HNMR (Bruker 400 MHz, DMSO-d6): 7.93 (s, 1H), 7.58 (dd, J=8.0, 1.5 Hz,1H), 7.41-7.29 (m, 2H), 7.20 (dd, J=7.6, 1.6 Hz, 1H), 4.61 (dd, J=19.0,14.6 Hz, 2H), 3.17-2.95 (m, 3H), 2.47-2.29 (m, 2H), 2.12-1.92 (m, 5H),1.86-1.51 (m, 4H), 1.44-1.28 (m, 2H), LC/MS (M+1): 470.2.

Compounds 98, 104, 99, 105:(5P)-2-[(3aR,6aS)-3a-(aminomethyl)-octahydrocyclopenta[c]pyrrol-2-yl]-6-amino-5-(2,3-dichlorophenyl)pyrimidine-4-carboxamide,(5P)-2-[(3aS,6aR)-3a-(aminomethyl)-octahydrocyclopenta[c]pyrrol-2-yl]-6-amino-5-(2,3-dichlorophenyl)pyrimidine-4-carboxamide,(5M)-2-[(3aR,6aS)-3a-(aminomethyl)-octahydrocyclopenta[c]pyrrol-2-yl]-6-amino-5-(2,3-dichlorophenyl)pyrimidine-4-carboxamide,(5M)-2-[(3aS,6aR)-3a-(aminomethyl)-octahydrocyclopenta[c]pyrrol-2-yl]-6-amino-5-(2,3-dichlorophenyl)pyrimidine-4-carboxamideStep 1:rac-2-[(3aS,6aR)-3a-(aminomethyl)-octahydrocyclopenta[c]pyrrol-2-yl]-6-amino-5-(2,3-dichlorophenyl)pyrimidine-4-carboxamide

The title compound was obtained following procedure described forcompound 85 but starting from 6-amino-2-chloropyrimidine-4-carbonitrile(250 mg, 1.6 mmol) and rac-tert-butyln-([(3ar,6ar)-octahydrocyclopenta[c]pyrrol-3a-yl]methyl)carbamatehydrochloride (Enamine, 895 mg, 3.2 mmol as a white amorphous solid (179mg, 25%, 5 steps). 1H NMR (400 MHz, DMSO-d6) δ 7.69 (s, 1H), 7.51 (d,J=8.0 Hz, 1H), 7.28 (t, J=7.8 Hz, 1H), 7.21-7.04 (m, 2H), 6.02 (s, 2H),3.80-3.36 (m, 4H), 3.06 (d, J=6.1 Hz, 2H), 2.56 (s, 2H), 2.35 (ddq,J=12.8, 8.4, 4.6, 4.1 Hz, 1H), 1.95-1.37 (m, 6H); LC/MS (M+1): 421.1.

Step 2: Separation of the Four Isomers

The isomers ofrac-2-[(3aS,6aR)-3a-(aminomethyl)-octahydrocyclopenta[c]pyrrol-2-yl]-6-amino-5-(2,3-dichlorophenyl)pyrimidine-4-carboxamidewereseparated by preparative SFC (column: IG, 250×21 mm, 5 micron,Methanol+20 mM NH₄OH:CO2, 30:70%).

Stereochemistry was assigned arbitrarily. Enantiomer purity was assessedby SFC using a chiral column IC (Methanol+20 mM NH₄OH).

First elutinq fraction (Compound 98): white amorphous solid, 26 mg,RT=3.76 min, ed=95.9%, 1H NMR (400 MHz, DMSO-d6) δ 7.68 (s, 1H), 7.51(dd, J=8.1, 1.6 Hz, 1H), 7.28 (t, J=7.8 Hz, 1H), 7.21-7.04 (m, 2H), 6.03(s, 2H), 3.65 (ddd, J=35.0, 11.5, 6.8 Hz, 2H), 3.26-3.19 (m, 1H),2.42-2.26 (m, 1H), 1.93-1.40 (m, 8H), 1.24 (d, J=3.0 Hz, 2H), 0.87 (dt,J=13.4, 7.2 Hz, 1H), LC/MS (M+1): 421.1

Second elutinq fraction (Compound 104): white amorphous solid, 35 mg,RT=3.82 min, ed=97.3%, 1H NMR (400 MHz, DMSO-d6) δ 7.69 (s, 1H), 7.51(dd, J=8.1, 1.6 Hz, 1H), 7.28 (t, J=7.8 Hz, 1H), 7.16 (s, 1H), 7.09 (dd,J=7.6, 1.6 Hz, 1H), 6.02 (s, 2H), 3.81-3.54 (m, 2H), 2.56 (s, 2H),2.43-2.19 (m, 2H), 1.95-1.36 (m, 8H), 1.36-1.13 (m, 1H); LC/MS (M+1):421.0

Third elutinq fraction (Compound 99): white amorphous solid, 46 mg,RT=4.14 min, ed=95.1%, 1H NMR (400 MHz, DMSO-d6) δ 7.69 (s, 1H), 7.51(dd, J=8.1, 1.6 Hz, 1H), 7.28 (t, J=7.8 Hz, 1H), 7.16 (s, 1H), 7.09 (dd,J=7.6, 1.6 Hz, 1H), 6.02 (s, 2H), 3.81-3.54 (m, 2H), 2.56 (s, 2H),2.43-2.19 (m, 2H), 1.95-1.36 (m, 8H), 1.36-1.13 (m, 1H); LC/MS (M+1):421.0

Fourth elutinq fraction (Compound 105): white amorphous solid, 29 mg,RT=4.2 min, ed=95.4%, 1H NMR (400 MHz, DMSO-d6) δ 7.69 (s, 1H), 7.51(dd, J=8.1, 1.5 Hz, 1H), 7.28 (t, J=7.8 Hz, 1H), 7.16 (s, 1H), 7.10 (dd,J=7.6, 1.6 Hz, 1H), 6.02 (s, 2H), 3.77-3.54 (m, 2H), 2.56 (s, 2H),2.43-2.22 (m, 2H), 1.94-1.41 (m, 8H), 1.24 (s, 1H).); LC/MS (M+1): 421.1

Compounds 100, 101, 102, 103:(5P)-2-[(3aR,7aS)-3a-(aminomethyl)-octahydro-1H-isoindol-2-yl]-6-amino-5-(2,3-dichlorophenyl)pyrimidine-4-carboxamide,(5P)-2-[(3aS,7aR)-3a-(aminomethyl)-octahydro-1H-isoindol-2-yl]-6-amino-5-(2,3-dichlorophenyl)pyrimidine-4-carboxamide,(5M)-2-[(3aR,7aS)-3a-(aminomethyl)-octahydro-1H-isoindol-2-yl]-6-amino-5-(2,3-dichlorophenyl)pyrimidine-4-carboxamide,(5M)-2-[(3aS,7aR)-3a-(aminomethyl)-octahydro-1H-isoindol-2-yl]-6-amino-5-(2,3-dichlorophenyl)pyrimidine-4-carboxamideStep 1:2-[3a-(aminomethyl)-octahydro-1H-isoindol-2-yl]-6-amino-5-(2,3-dichlorophenyl)pyrimidine-4-carboxamide

The title compound was obtained following procedure described forcompound 85 but starting from 6-amino-2-chloropyrimidine-4-carbonitrile(250 mg, 1.6 mmol) and tert-butyln-(octahydro-1h-isoindol-3a-ylmethyl)carbamate (Enamine, 823 mg, 3.2mmol as a white amorphous solid (128 mg, 19%, 5 steps). 1H NMR (400 MHz,DMSO-d6) δ 7.68 (s, 1H), 7.50 (d, 1H), 7.28 (t, J=7.8 Hz, 1H), 7.23-7.04(m, 2H), 6.00 (s, 2H), 3.70-3.34 (m, 4H), 2.63 (q, J=5.8 Hz, 1H), 2.05(dd, J=11.5, 5.8 Hz, 2H), 1.72-1.20 (m, 8H); LC/MS (M+1): 435.1.

Step 2: Separation of the Four Isomers

The isomers of2-[3a-(aminomethyl)-octahydro-1H-isoindol-2-yl]-6-amino-5-(2,3-dichlorophenyl)pyrimidine-4-carboxamidewere separated by preparative SFC (column: IG, 250×21 mm, 5 micron,Methanol+20 mM NH₄OH:CO2, 30:70%). Stereochemistry was assignedarbitrarily. Enantiomer purity was assessed by SFC using a chiral columnIG (Methanol+20 mM NH₄OH).

First eluting fraction (Compound 100): white amorphous solid, 20 mg,RT=3.67 min, ed=95.0%, 1H NMR (400 MHz, DMSO-d6): 7.68 (s, 1H), 7.51(dd, J=8.0, 1.5 Hz, 1H), 7.28 (t, J=7.8 Hz, 1H), 7.22-7.05 (m, 2H), 6.00(s, 2H), 3.77-3.48 (m, 2H), 2.62 (d, J=14.0 Hz, 2H), 2.04 (s, 2H),1.69-1.17 (m, 10H), 0.95-0.74 (m, 1H)., LC/MS (M+1): 435.0

Second elutinq fraction (Compound 101): white amorphous solid, 19 mg,RT=3.59 min, ed=93.4%, 1H NMR (400 MHz, DMSO-d6): 7.76-7.59 (m, 1H),7.51 (dd, J=8.1, 1.6 Hz, 1H), 7.28 (t, J=7.8 Hz, 1H), 7.22-7.04 (m, 2H),6.00 (s, 2H), 3.73-3.43 (m, 2H), 2.64 (d, J=14.3 Hz, 1H), 2.15-1.89 (m,2H), 1.40 (t, J=56.6 Hz, 9H), 0.96-0.72 (m, 1H); LC/MS (M+1): 435.0

Third elutinq fraction (Compound 102): white amorphous solid, 20 mg,RT=3.85 min, ed=91.3%, 1H NMR (400 MHz, DMSO-d6): 7.68 (s, 1H), 7.51(dd, J=8.0, 1.6 Hz, 1H), 7.28 (t, J=7.8 Hz, 1H), 7.22-7.01 (m, 2H), 6.00(s, 2H), 3.73-3.43 (m, 2H), 2.64 (s, 2H), 2.03 (dt, J=15.3, 7.2 Hz, 2H),1.78-0.97 (m, 10H), 0.97-0.68 (m, 1H). LC/MS (M+1): 435.0

Fourth eluting fraction (Compound 103): white amorphous solid, 16 mg,RT=4.02 min, ed=94.2%, 1H NMR (400 MHz, DMSO-d6): 7.68 (s, 1H), 7.51 (d,J=7.8 Hz, 1H), 7.28 (q, J=7.0, 6.3 Hz, 1H), 7.22-7.00 (m, 2H), 6.00 (s,2H), 3.51 (s, 2H), 2.04 (s, 2H), 1.34 (d, J=77.2 Hz, 11H), 0.85 (s, 2H);LC/MS (M+1): 435.1

Compound 113 and 114:(5P)-2-[(1R)-1-amino-8-azaspiro[4.5]decan-8-yl]-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carboxamideand(5M)-2-[(1R)-1-amino-8-azaspiro[4.5]decan-8-yl]-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carboxamide

The title compounds were obtained following procedure described forcompound 85 but starting from tert-butylN-[(1R)-8-(5-bromo-4-cyano-6-methylpyrimidin-2-yl)-8-azaspiro[4.5]decan-1-yl]carbamate(intermediate 13, 100 mg; 0.22 mmol) and 2,3-dichlorophenylboronic acid(64 mg; 0.33 mmol) as a white powder (43 mg, 31% for three steps,mixture of the two atropisomers).

The two atropisomers were separated by preparative SFC (column Whelk-O,250×21 mm, 5 micron,Methanol+20 mM NH₄OH: CO2, 5-45).

First elutinq isomer (compound 113): white solid, 9 mg, RT=3.51 min,ed=100%, 1H NMR (400 MHz, DMSO-d6): 7.91 (s, 1H), 7.58 (dd, J=8.0, 1.5Hz, 1H), 7.43-7.29 (m, 2H), 7.20 (dd, J=7.6, 1.6 Hz, 1H), 4.55 (t,J=13.0 Hz, 2H), 3.15-3.05 (m, 2H), 2.78 (t, J=7.4 Hz, 1H), 2.00 (s, 3H),1.96-1.72 (m, 3H), 1.73-1.29 (m, 7H), 1.29-1.14 (m, 2H), LC/MS (M+1):434.0.

Second elutinq isomer (compound 114): white solid, 9 mg, RT=4.03 min,ed=94.3%, 1H NMR (400 MHz, DMSO-d6): 7.90 (s, 1H), 7.58 (dd, J=8.1, 1.6Hz, 1H), 7.40-7.30 (m, 2H), 7.20 (dd, J=7.6, 1.6 Hz, 1H), 4.54 (td,J=9.5, 5.1 Hz, 2H), 3.20-3.05 (m, 2H), 2.73 (t, J=7.4 Hz, 1H), 2.00 (s,3H), 1.94-1.76 (m, 2H), 1.75-1.47 (m, 5H), 1.46-1.31 (m, 2H), 1.31-1.13(m, 3H), LC/MS (M+1): 434.0.

Compounds 117 and 118:(5P)-6-amino-2-[(1S)-1-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl]-5-(2,3-dichlorophenyl)pyrimidine-4-carboxamideand(5M)-6-amino-2-[(1S)-1-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl]-5-(2,3-dichlorophenyl)pyrimidine-4-carboxamideStep 1:6-amino-2-[(1S)-1-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl]-5-(2,3-dichlorophenyl)pyrimidine-4-carbonitrile

A solution of6-Amino-5-(2,3-dichloro-phenyl)-2-methanesulfonyl-pyrimidine-4-carbonitrile(75 mg; 0.22 mmol; 1.00 eq.),(3S)-1,3-dihydrospiro[indene-2,4′-piperidin]-3-amine dihydrochloride(Pharmablock, 90 mg; 0.33 mmol; 1.50 eq.) and potassium carbonate (151mg; 1.09 mmol; 5.00 eq.) in MeCN (1.50 ml; 20.00 V) andN,N-Dimethylformamide (0.75 ml; 10.00 V) was stirred at 100° C. for 18hrs. The reaction mixture was diluted with EtOAc (40 mL) and was washedwith water (2×10 mL) and brine (10 mL). The organic layer was dried oversodium sulfate, filtered and concentrated. Purification by flashchromatography on silica (EtOAc:MeOH, gradient from 99:1 to 90:10)afforded the title compound as a white solid (76 mg, 75%).

1H NMR (Bruker 400 MHz, DMSO-d6): 7.72 (dd, J=8.0, 1.7 Hz, 1H), 7.45 (t,J=7.8 Hz, 1H), 7.39 (dd, J=7.6, 1.6 Hz, 1H), 7.30 (dd, J=6.6, 1.7 Hz,1H), 7.22-7.10 (m, 3H), 7.00-6.57 (m, 2H), 4.44 (t, J=14.2 Hz, 2H), 3.83(s, 1H), 3.21-3.02 (m, 3H), 2.62 (d, J=15.6 Hz, 1H), 1.93-1.78 (m, 2H),1.78-1.67 (m, 1H), 1.59 (td, J=12.6, 4.3 Hz, 1H), 1.48 (d, J=13.2 Hz,1H), 1.07 (d, J=13.3 Hz, 1H). LC/MS (M+1): 465.2.

Step 2:(5P)-6-amino-2-[(1S)-1-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl]-5-(2,3-dichlorophenyl)pyrimidine-4-carboxamideand(5M)-6-amino-2-[(1S)-1-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl]-5-(2,3-dichlorophenyl)pyrimidine-4-carboxamide

A solution of6-amino-2-[(1S)-1-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl]-5-(2,3-dichlorophenyl)pyrimidine-4-carbonitrile(936 mg; 2.01 mmol), potassium carbonate (1.39 g; 10.1 mmol) andhydrogen peroxide, 30% weight (4.1 ml; 36.2 mmol) in DMSO (23 mL) wasstirred at 50° C. for 4 h. The reaction mixture was diluted with EtOAc(800 mL) and washed with a solution of sodium thiosulfate pentahydrate(27 g; 109 mmol) in water (230 mL). The organic layer was washed withwater (2×400 mL) and brine (400 mL), dried over sodium sulfate, filteredand concentrated to give the title compound as a white solid (970 mg).

The two atropisomers were separated by preparative SFC (column IC,250×21 mm, 5 micron; methanol+20 mM NH₄OH: CO₂, 45-55)

First eluting isomer (compound 117): white solid, 309 mg, RT=6.62 min,ed=100%, LC/MS (M+1) 483.1.

Second eluting isomer (compound 118): white solid, 328 mg, RT=7.98 min,ed=99.4%, 1H NMR (400 MHz, DMSO-d6): 7.74 (s, 1H), 7.53-7.50 (m, 1H),7.37-7.25 (m, 2H), 7.25-7.15 (m, 4H), 7.12-7.10 (m, 1H), 6.12 (s, 2H),4.54 (d, J=13.7 Hz, 2H), 3.90 (s, 1H), 3.16-3.01 (m, 3H), 2.67 (d,J=15.6 Hz, 1H), 1.79-1.68 (m, 1H), 1.64 ? 1.58 (m, 1H), 1.47 (d, J=13.0Hz, 1H), 1.12 (d, J=13.0 Hz, 1H); LC/MS (M+1) 483.1.

Compound 119 and 120:(M)-2-[(1S)-1-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl]-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carboxamideand(P)-2-[(1S)-1-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl]-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carboxamideStep 1:6-methyl-2-{1-oxo-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl}pyrimidine-4-carbonitrile

A solution of 2-chloro-6-methylpyrimidine-4-carbonitrile(120 mg, 0.742mmol), 1H-spiro[indene-2,4-piperidin]-3-one hydrochloride (Pharmablock,279 mg, 1.114 mmol) and DIEA (303 mg, 2.23 mmol) in MeCN (5.0 mL wasstirred for 2 h at 80° C. under nitrogen atmosphere. The resultingmixture was concentrated under vacuum and purified by flashchromatography on silica (PE:EtOAC, 1:1) to afford the title compound asa white solid (200 mg,84%); LC/MS (M+1): 319.0.

Step 2:5-bromo-6-methyl-2-{1-oxo-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl}pyrimidine-4-carbonitrile

A solution of6-methyl-2-[3-oxo-1H-spiro[indene-2,4-piperidin]-1-yl]pyrimidine-4-carbonitrile(180 mg, 0.565 mmol) and NBS (158 mg, 0.847) in DMF (5.0 mL) was stirredfor 1 h at room temperature. The reaction was quenched with Water andextracted with EtOAc (3×30 mL). The combined organic layers were washedwith brine (1×30 mL), dried over anhydrous sodium sulfate, filtered andconcentrated. Purification by flash chromatography on silica (PE: EtOAc,5:1) afforded the title compound as a yellow solid (220 mg, 96.38%).LC/MS (M+1): 396.9.

Step 3:5-(2,3-dichlorophenyl)-6-methyl-2-{3-oxo-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl}pyrimidine-4-carbonitrile

A mixture of5-bromo-6-methyl-2-[3-oxo-1H-spiro[indene-2,4-piperidin]-1-yl]pyrimidine-4-carbonitrile(590 mg, 1.46 mmol), 2,3-dichlorophenylboronic acid (880 mg, 4.38 mmol),K₃PO₄ (978 mg, 4.38 mmol), XPhos Pd G3 (130 mg, 0.146 mmol) and XPhos(73 mg, 0.146 mmol) in 1,4-dioxane (5 mL) and water (3 mL) was stirredfor 2 h at 100° C. under a nitrogen atmosphere. The resulting mixturewas concentrated under reduced pressure and purified by Prep-TLC onsilica (PE:EtOAc, 1:1) to afford the title compound as a yellow solid(820 mg, 81%). LC/MS (M+1): 463.2.

Step 4:(R)-N-{1′-[4-cyano-5-(2,3-dichlorophenyl)-6-methylpyrimidin-2-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-3-ylidene}-2-methylpropane-2-sulfinamide

A mixture of5-(2,3-dichlorophenyl)-6-methyl-2-[3-oxo-1H-spiro[indene-2,4-piperidin]-1-yl]pyrimidine-4-carbonitrile(780 mg, 1.34 mmol) and (R)-2-methylpropane-2-sulfinamide (681 mg, 5.340mmol) in Ti(OEt)₄ (12.3 g, 53.5 mmol) was stirred for 2 h at 90° C.under nitrogen atmosphere. The reaction mixture was then diluted withwater and EtOAc and filtered. The filter cake was washed with EtOAc (100mL) and the filtrate was concentrated under reduced pressure. Theaqueous layer was extracted with EtOAc (3×120 mL). Combined organiclayers were dried over sodium sulfate, filtered and concentrated.Purification by flash chromatography on silica (PE:EtOAc, 1:1) affordedthe title compound as a yellow solid (800 mg, 64%). LC/MS (M+1):566.2.

Step 5:(R)-N-[(3S)-1′-[4-cyano-5-(2,3-dichlorophenyl)-6-methylpyrimidin-2-yl]-1,3-dihydrospiro[indene-2,4′-piperidin]-3-yl]-2-methylpropane-2-sulfinamide

A solution of NaBH₄ (93 mg, 2.34 mmol) in water (1.3 mL) was slowlyadded to a solution of(R)-N-[1-[4-cyano-5-(2,3-dichlorophenyl)-6-methylpyrimidin-2-yl]-1H-spiro[indene-2,4-piperidin]-3-ylidene]-2-methylpropane-2-sulfinamide(440 mg, 0.468 mmol) in THF (8.8 mL) maintained at −50° C. The resultingmixture was stirred for 1 h at 25° C. under N₂ atmosphere. The reactionwas quenched by the addition of Water/Ice (30 mL) and the aqueous layerwas extracted with EtOAc (3×50 mL). Combined organic layers were driedover sodium sulfate, filtered and concentrated to give the titlecompound as a yellow oil (320 mg, 63%). LC/MS (M+1): 568.2.

Step 6:5-(2,3-dichlorophenyl)-6-methyl-2-[(3S)-3-{[(R)-2-methylpropane-2-sulfinyl]amino}-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl]pyrimidine-4-carboxamide

Into a 30 mL sealed tube were added A mixture of(R)-N-[(3S)-1-[4-cyano-5-(2,3-dichlorophenyl)-6-methylpyrimidin-2-yl]-1,3-dihydrospiro[indene-2,4-piperidin]-3-yl]-2-methylpropane-2-sulfinamide(300 mg, 0.275 mmol) and NaOH (200 mg, 4.750 mmol) in EtOH (5.00 mL) andwater (5 mL) was stirred for 1 h at 70° C. under nitrogen atmosphere ina sealed tube. The reaction mixture was then extracted with EtOAc (3×30mL). Combined organic layers were dried over sodium sulfate, filteredand concentrated to give the title compound as a yellow solid (400 mg,88%). LC/MS (M+1): 586.2.

Step 7:2-[(1S)-1-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl]-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carboxamide

A solution of5-(2,3-dichlorophenyl)-6-methyl-2-[(1S)-1-[[(R)-2-methylpropane-2-sulfinyl]amino]-1,3-dihydrospiro[indene-2,4-piperidin]-1-yl]pyrimidine-4-carboxamide(100 mg, 0.17 mmol) and HCl(gas)in 1,4-dioxane (2.00 mL, 7.9 mmol, 12%)was stirred for 1 h at 25° C. under nitrogen atmosphere. The solvent wasremoved under reduced pressure and the residue was purified by reverseflash chromatography on C18 silica gel (ACN: water+NH₄OH, gradient from0:100 to 50:50) to give the title compound as a white solid (50 mg,60%). 1H NMR (400 MHz, DMSO-d6): 7.94 (s, 1H), 7.58 (d, J=7.9 Hz, 1H),7.41-7.29 (m, 3H), 7.24-7.14 (m, 4H), 4.62 (t, J=15.0 Hz, 2H), 3.86 (s,1H), 3.17 (s, 1H), 3.10 (d, J=15.7 Hz, 1H), 2.66 (d, J=15.5 Hz, 1H),2.01 (s, 3H), 1.82-1.71 (m, 1H), 1.64 (dd, J=13.7, 9.4 Hz, 1H), 1.52 (d,J=13.1 Hz, 1H), 1.13 (d, J=13.4 Hz, 1H). LC/MS (M+1): 482.2.

Step 8: atropisomers separation:(5M)-2-[(1S)-1-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl]-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carboxamideand(5P)-2-[(1S)-1-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl]-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carboxamide

The atropisomers from2-[(1S)-1-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl]-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carboxamidewere separated by preparative HPLC (column (R,R)whelk-01, 4.6*50 mm, 3.5um, Hexane+0.1% DEA:EtOH, 50:50).

First eluting isomer (compound 119): 29 mg, RT=1.1 min, ed=97.9; 1H NMR(400 MHz, DMSO-d6): 7.94 (s, 1H), 7.58 (dd, J=8.1, 1.5 Hz, 1H),7.41-7.29 (m, 3H), 7.19 (ddd, J=15.5, 7.2, 2.8 Hz, 4H), 4.62 (t, J=16.3Hz, 2H), 3.86 (s, 1H), 3.25-3.15 (m, 1H), 3.11 (d, J=15.7 Hz, 1H), 2.66(d, J=15.4 Hz, 1H), 2.01 (s, 3H), 1.77 (t, J=11.3 Hz, 1H), 1.62 (d,J=11.9 Hz, 1H), 1.52 (d, J=12.9 Hz, 1H), 1.13 (d, J=13.0 Hz, 1H). LC/MS(M+1): 481.2, mp: 114-115° C.

Second eluting isomer (compound 120): 19 mg, RT=6.9 min, ed=98.5, LC/MS(M+1): 481.2, mp: 121-123° C.

Compound 121:6-amino-2-[(4S)-4-amino-4,6-dihydrospiro[cyclopenta[d][1,3]thiazole-5,4′-piperidin]-1′-yl]-5-(2,3-dichlorophenyl)pyrimidine-4-carboxamideStep 1:6-amino-2-[(4S)-4-amino-4,6-dihydrospiro[cyclopenta[d][1,3]thiazole-5,4′-piperidin]-1′-yl]-5-(2,3-dichlorophenyl)pyrimidine-4-carbonitrile

A mixture of(4S)-4,6-dihydrospiro[cyclopenta[d][1,3]thiazole-5,4-piperidin]-4-amine(Intermediate16, 100 mg, 0.430 mmol),6-amino-5-(2,3-dichlorophenyl)-2-methanesulfonylpyrimidine-4-carbonitrile(220mg, 0.439 mmol) and K₂CO₃ (10 mg, 0.069 mmol) in ACN (4.0 mL) wasstirred for 12 h at RT under nitrogen atmosphere. Solvent was removedunder reduced pressure and the residue was purified by chromatography onsilica (PE:EtOAc, 1:9) to afford the title compound as a yellow solid(60 mg,24%). LC/MS (M+1): 472.1.

Step 2:6-amino-2-[(4S)-4-amino-4,6-dihydrospiro[cyclopenta[d][1,3]thiazole-5,4′-piperidin]-1′-yl]-5-(2,3-dichlorophenyl)pyrimidine-4-carboxamide

A solution of6-amino-2-[(4S)-4-amino-4,6-dihydrospiro[cyclopenta[d][1,3]thiazole-5,4-piperidin]-1-yl]-5-(2,3-dichlorophenyl)pyrimidine-4-carbonitrile(40 mg, 0.070 mmol), NaOH (73 mg, 1.73 mmol) in water (1 mL) and EtOH (1mL) was stirred for 1 h at 50° C. Solvent was removed under reducedpressure and the residue was purified by preparative HPLC (columnXBridge, Prep C18 OBD, 19×150 mm, 5 um, Water+10 mmol NH₄HCO₃): ACN;Gradient from 70:30 to 50:50 in 8 min) to give the title compound as anoff-white solid (5.6 mg, 16%). 1H NMR (400 MHz, DMSO-d6): 8.96 (s, 1H),7.74 (s, 1H), 7.52 (dd, J=8.0, 1.5 Hz, 1H), 7.29 (t, J=7.8 Hz, 1H), 7.16(s, 1H), 7.11 (d, J=7.5 Hz, 1H), 6.11 (s, 1H), 4.44 (dd, J=21.6, 14.3Hz, 2H), 3.98 (s, 1H), 3.25 ? 3.17 (m, 2H), 2.87 (d, J=15.3 Hz, 1H),2.75 (d, J=15.3 Hz, 1H), 1.82-1.71 (m, 1H), 1.68-1.50 (m, 3H), 1.24 (s,1H), LC/MS (M+1): 490.1.

Compound 122:2-((S)-3-amino-3H-spiro[benzofuran-2,4′-piperidin]-1′-yl)-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carboxamideStep 1:6-methyl-2-[3-oxospiro[1-benzofuran-2,4-piperidin]-1-yl]pyrimidine-4-carbonitrile

A solution of 2-chloro-6-methylpyrimidine-4-carbonitrile (100 mg, 0.619mmol), spiro[1-benzofuran-2,4-piperidin]-3-one (140 mg, 0.682 mmol) andDIEA (0.215 mL, 1.24 mmol, 2 equiv) in CAN (4.0 mL) was stirred for 2 hat 80° C. The resulting mixture was cooled down to room temperature andconcentrated under vacuum. The residue was purified by silica gel columnchromatography (PE/EtOAc, 1:1) to afford the title compound as ayellowsolid (120 mg, 54%). LC/MS (M+1): 321

Step 2:5-bromo-6-methyl-2-[3-oxospiro[1-benzofuran-2,4′-piperidin]-1′-yl]pyrimidine-4-carbonitrile

NBS (105 mg, 0.563 mmol) was added to a solution of6-methyl-2-[3-oxospiro[1-benzofuran-2,4-piperidin]-1-yl]pyrimidine-4-carbonitrile(100 mg, 0.281 mmol) in DMF (5.0 mL) at 25° C. The resulting mixture wasstirred for 2 h at 25° C. It was then diluted with water (40 mL) andextracted with EtOAc (3×45 mL). Combined organic layers were washed withbrine (1×100 mL), dried over anhydrous sodium sulfate, filtered andconcentrated to give the title compound as a yellow solid (110 mg, 85%yield). LC/MS (M+1): 399, 401.

Step 3:5-(2,3-dichlorophenyl)-6-methyl-2-{3-oxo-3H-spiro[1-benzofuran-2,4′-piperidin]-1′-yl}pyrimidine-4-carbonitrile

A solution of5-bromo-6-methyl-2-[3-oxospiro[1-benzofuran-2,4-piperidin]-1-yl]pyrimidine-4-carbonitrile(100 mg, 0.216 mmol), 2,3-dichlorophenylboronic acid (87 mg, 0.432mmol), K₃PO₄ (145 mg, 0.648 mmol), XPhos (22 mg, 0.043 mmol) and XPhosPd G3 (39 mg, 0.043 mmol) in 1,4-dioxane (2 mL) and water (0.5 mL) wasstirred for 2 h at 100° C. The resulting mixture was cooled down to roomtemperature, and then concentrated under reduced pressure. The residuewas diluted with DCM (5 mL), filtered and the filtrate was concentratedunder vacuum. The residue was purified by flash chromatography on silica(PE/EtOAc, 1:1) to afford the title compound as a yellow solid (95mg,78%). LC/MS (M+1): 465.

Step 4:(S)-N-((E)-1′-(4-cyano-5-(2,3-dichlorophenyl)-6-methylpyrimidin-2-yl)-3H-spiro[benzofuran-2,4′-piperidin]-3-ylidene)-2-methylpropane-2-sulfinamide

A mixture of5-(2,3-dichlorophenyl)-6-methyl-2-[3-oxospiro[1-benzofuran-2,4-piperidin]-1-yl]pyrimidine-4-carbonitrile(90 mg, 0.18 mmol), (S)-2-methylpropane-2-sulfinamide (138 mg, 1.08mmol) and Ti(OEt)₄ (1 mL) was stirred for 4 h at 90° C. The resultingmixture was cooled to room temperature, poured into a mixture of water(20 mL) and EtOAc (20 mL) and filtered. The two layers from the filtratewere separated and the aqueous phase was extracted with EtOAc (3×20 mL).Combined organic layers were dried over anhydrous sodium sulfate,filtered and concentrated. Purification by flash chromatography onsilica (PE/EtOAc, 1:1) afforded the title compound as an off-white solid(180 mg, 100% yield). LC/MS (M+1): 568.2.

Step 5:2-((S)-3-((tert-butylthio)amino)-3H-spiro[benzofuran-2,4′-piperidin]-1′-yl)-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carbonitrile

NaBH₄ (31 mg, 0.782 mmol) was added to a solution of(S)-N-[1-[4-cyano-5-(2,3-dichlorophenyl)-6-methylpyrimidin-2-yl]spiro[1-benzofuran-2,4-piperidin]-3-ylidene]-2-methylpropane-2-sulfinamide(160 mg, 0.156 mmol) in THF (4.0 mL) and H₂O (1.0 mL) maintained at −50°C. under nitrogen atmosphere. The resulting mixture was stirred for 1 hat 25° C. It was then poured into water (10 mL) and extracted with EtOAc(3×10 mL). Combined organic layers were washed with brine (1×30 mL),dried over anhydrous sodium sulfate, filtered and concentrated to givethe title compound as a yellow solid (130 mg, 94% yield). LC/MS (M+1):554, 556.

Step 6:2-((S)-3-((tert-butylthio)amino)-3H-spiro[benzofuran-2,4′-piperidin]-1′-yl)-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carboxamide

A mixture of(S)-N-[(3S)-1-[4-cyano-5-(2,3-dichlorophenyl)-6-methylpyrimidin-2-yl]-3H-spiro[1-benzofuran-2,4-piperidin]-3-yl]-2-methylpropane-2-sulfinamide(130 mg, 0.142 mmol), NaOH aqueous (1.5 mL, 2M) and EtOH (3.0 mL) wasstirred for 1 h at 70° C. The mixture was cooled down to roomtemperature and the solvent removed under reduced pressure. The residualaqueous layer was extracted with EtOAc (3×5 mL). Combined organic layerswere dried over sodium sulfate, filtered and concentrated. Purificationby flash chromatography on silica (PE:EtOAc, 1:1) afforded the titlecompound as a yellow solid (120 mg, 94% yield) as a yellow solid. LC/MS(M+1): 572, 574.

Step 7:2-((S)-3-amino-3H-spiro[benzofuran-2,4′-piperidin]-1′-yl)-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carboxamide

A mixture of5-(2,3-dichlorophenyl)-6-methyl-2-[(3S)-3-[[(S)-2-methylpropane-2-sulfinyl]amino]-3H-spiro[1-benzofuran-2,4-piperidin]-1-yl]pyrimidine-4-carboxamide(70 mg, 0.113 mmol) and HCl/1,4-dioxane (7 mL of a 4M solution) wasstirred for 2 h at 25° C. The resulting mixture was concentrated undervacuum and purified by reverse phase chromatography (Column: C18 silicagel; water+10 mmol/L NH₄HCO₃: ACN, gradient from 0% to 70% in 40 min) togive the title compound as an off-white solid (45.7 mg, 84%) ¹H-NMR (400MHz, DMSO-d₆): 8.00 (brs, 1H), 7.59 (dd, J=8.0, 1.2 Hz, 1H), 7.41-7.33(m, 3H), 7.22-7.14 (m, 2H), 6.88 (t, J=7.2 Hz, 1H), 6.80 (d, J=7.6 Hz,1H), 4.68-4.57 (m, 2H), 4.13 (s, 1H), 3.49-3.33 (m, 2H), 2.03 (s, 3H),1.94-1.70 (m, 4H). LC/MS (M+1): m/z=484.1

Compound 123:6-amino-2-((R)-3-amino-3H-spiro[benzofuran-2,4′-piperidin]-1′-yl)-5-(2,3-dichlorophenyl)pyrimidine-4-carboxamidedihydrochloride Step 1:6-amino-2-[(3S)-3-amino-3H-spiro[1-benzofuran-2,4′-piperidin]-1′-yl]-5-(2,3-dichlorophenyl)pyrimidine-4-carbonitrile

A solution of6-amino-5-(2,3-dichlorophenyl)-2-methanesulfonylpyrimidine-4-carbonitrile(192 mg, 0.492 mmol), (3R)-3H-spiro[1-benzofuran-2,4′-piperidin]-3-amine(intermediate 14, 204 mg, 0.985 mmol) and K₂CO₃ (143 mg, 0.985 mmol) inDMF (10 mL) was stirred for 2 h at 100° C. The reaction mixture wascooled down to room temperature, poured into water (50 mL) and extractedwith EtOAc (3×50 mL). Combined organic layers were dried over anhydroussodium sulfate, filtered and concentrated. Purification by flashchromatography on silica (DCM:MeOH, 10:1) afforded the title compound asa yellow solid (100 mg, 29% yield) as a yellow solid. LC/MS: 467.

Step 2:6-amino-2-((R)-3-amino-3H-spiro[benzofuran-2,4′-piperidin]-1′-yl)-5-(2,3-dichlorophenyl)pyrimidine-4-carboxamidedihydrochloride

A mixture of6-amino-2-[(3R)-3-amino-3H-spiro[1-benzofuran-2,4-piperidin]-1-yl]-5-(2,3-dichlorophenyl)pyrimidine-4-carbonitrile(30 mg, 0.043 mmol), NaOH aqueous (0.5 mL, 2M) and EtOH (0.50 mL) wasstirred for 30 min at 70° C. The resulting mixture was cooled to roomtemperature, concentrated and purified by reverse phase chromatography(Column: C18 silica gel; water+0.05% HCl: CH₃CN, Gradient from 0% to 70%in 40 min) to give the title compound as an off-white solid (6.6 mg,26%). ¹H-NMR (400 MHz, DMSO-d₆): 7.78 (s, 1H), 7.52 (dd, J=8.0, 1.6 Hz,1H), 7.33-7.27 (m, 2H), 7.18-7.10 (m, 3H), 6.86 (t, J=7.6 Hz, 1H), 6.78(d, J=8.0 Hz, 1H), 6.16 (br s, 2H), 4.57-4.47 (m, 2H), 4.08 (s, 1H),3.25-3.20 (m, 2H), 1.90-1.80 (m, 1H), 1.78-1.68 (m, 3H), LC/MS (M+1):485.2.

Compounds 124,125,126, 127:(4M)-2-[(3R)-3-amino-3H-spiro[furo[2,3-b]pyridine-2,4′-piperidin]-1′-yl]-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carboxamide,(4M)-2-[(3S)-3-amino-3H-spiro[furo[2,3-b]pyridine-2,4′-piperidin]-1′-yl]-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carboxamide,(4P)-2-[(3R)-3-amino-3H-spiro[furo[2,3-b]pyridine-2,4′-piperidin]-1′-yl]-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carboxamide,(4P)-2-[(3S)-3-amino-3H-spiro[furo[2,3-b]pyridine-2,4′-piperidin]-1′-yl]-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carboxamideStep 1:2-[3-amino-3H-spiro[furo[2,3-b]pyridine-2,4′-piperidin]-1′-yl]-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carbonitrile

A solution of2-chloro-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carbonitrile (1.10g, 3.65 mmol),3H-spiro[furo[2,3-b]pyridine-2,4-piperidin]-3-amine(Intermediate 15,1.15 g, 5.47 mmol) and DIEA (1.81 mL, 11.0 mmol) in ACN (12 mL) wasstirred for 0.5 h at 80° C. The resulting mixture was concentrated underreduced pressure and purified by flash chromatography on silica(PE:EtOAc, 1:1) to afford the title compound as a yellow solid (1.4 g,81%). LC/MS (M+1): 467.1.

Step 2:2-[3-amino-3H-spiro[furo[2,3-b]pyridine-2,4′-piperidin]-1′-yl]-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carboxamide

A mixture of2-[3-amino-3H-spiro[furo[2,3-b]pyridine-2,4-piperidin]-1-yl]-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carbonitrile(0.80 g, 1.70 mmol), NaOH (0.16 g, 3.80 mmol), EtOH (4 mL) and H₂O (4mL) was stirred for 0.5 h at 70° C. The mixture cooled down to roomtemperature and neutralized to pH 7 by addition of 6M HCl. The resultingmixture was concentrated under reduced pressure and purified by reversephase chromatography (Colum: C18 silica gel; water+containing 10 mmol/LNH₄HCO₃: ACN; Gradient from 10% to 50% in 30 min) to afford2-[3-amino-3H-spiro[furo[2,3-b]pyridine-2,4-piperidin]-1-yl]-5-(2,3-dichlorophenyl)-6-methylpyrimidine-4-carboxamide(700 mg,79%) as white solid. LC/MS (M+1): 485.

Step 3: Isomers Separation

A first separation by preparative HPLC (Column CHIRALPAK IC, 3×25 cm,5um, Hexane+8 mmol/L NH₃·MeOH: EtOH; 50%) afforded two fractions:Fraction A (130 mg) (RT:9.6 min) and Fraction B (300 mg) (RT: 14.64min).

Isomers from fraction A were separated by preparative HPLC (ColumnCHIRALPAK IA, 3×25 cm, 5 um, MTBE+10 mM NH₃-MEOH:EtOH, 20%).

First elutinq isomer (124): 56 mg, RT: 11 min, ¹H NMR (400 MHz, DMSO-d₆)δ 8.00 (s, 2H), 7.72 (d, J=7.2, 1H), 7.59 (dd, J=8.0, 1.6 Hz, 1H),7.43-7.33 (m, 2H), 7.21 (dd, J=8.0, 1.6 Hz, 1H), 6.92 (dd, J=7.2, 5.2Hz, 1H), 4.71-4.61 (m, 2H), 4.14 (s, 1H), 3.51-3.39 (m, 2H), 2.20 (brs,2H), 2.03 (s, 3H), 1.94-1.77 (m, 4H); LC/MS (M+1): 485.1; RT=1.82 min(analytical column−chiral pack IA, MtBE+0.1% DEA:EtOH, 80:20), purity:100%.

Second elutinq isomer (125): 60 mg, RT: 12.9 min, ¹H NMR (400 MHz,DMSO-d₆): 8.01-8.00 (m, 2H), 7.72 (d, J=6.8 Hz, 1H), 7.59 (dd, J=8.0,1.2 Hz, 1H), 7.40-7.34 (m, 2H), 7.22 (dd, J=7.6, 1.6 Hz, 1H), 6.92 (dd,J=7.2, 5.2 Hz, 1H), 4.72-4.61 (m, 2H), 4.14 (s, 1H), 3.51-3.39 (m, 2H),2.20 (brs, 2H), 2.03 (s, 3H), 1.96-1.76 (m, 4H); LC/MS (M+1): 485.1;RT=2.26 min (analytical column−chiral pack IA, MtBE+0.1% DEA: EtOH,80:20); purity: 99.5%.

Isomers from fraction B were separated by preparative HPLC (CHIRALPAKID, 3×25 cm, 5 um, MTBE+10 mM NH₃-MEOH: EtOH, 15%).

First elutinq isomer (126): 92 mg, RT: 12.0 min; ¹H NMR (400 MHz,DMSO-d₆): 8.01-8.00 (m, 2H), 7.72 (d, J=6.4, 1H), 7.59 (dd, J=8.0, 1.6Hz, 1H), 7.41-7.34 (m, 2H), 7.22 (dd, J=7.6, 1.6 Hz, 1H), 6.91 (dd,J=7.2, 5.2 Hz, 1H), 4.72-4.61 (m, 2H), 4.14 (s, 1H), 3.49-3.39 (m, 2H),2.15 (brs, 2H), 2.03 (s, 3H), 1.93-1.77 (m, 4H), RT=2.33 min (analyticalcolumn−chiral pack AD, MtBE+0.1% DEA:EtOH,85:15); purity: 100%.

Second eluting isomer (127): 111 mg, RT: 15.5 min, ed=99.1%, ¹H NMR (400MHz, DMSO-d₆): 8.01-8.00 (m, 2H), 7.71 (d, J=6.8 Hz, 1H), 7.59 (dd,J=8.0, 1.2 Hz, 1H), 7.40-7.34 (m, 2H), 7.22 (dd, J=7.6, 1.2 Hz, 1H),6.92 (dd, J=6.8, 4.8 Hz, 1H), 4.71-4.61 (m, 2H), 4.14 (s, 1H), 3.49-3.39(m, 2H), 2.19 (br s, 2H), 2.03 (s, 3H), 1.91-1.77 (m, 4H); LC/MS (M+1):485.1; RT=3.17 min (analytical column Chiralpak ID, MtB+0.1% DEA: EtOH,85:15). purity: 99.1.

Compounds 128, 129, 130, 131:(4P)-6-amino-2-[(3R)-3-amino-3H-spiro[furo[2,3-b]pyridine-2,4-piperidin]-1-yl]-5-(2,3-dichlorophenyl)pyrimidine-4-carboxamide,(4P)-6-amino-2-[(3S)-3-amino-3H-spiro[furo[2,3-b]pyridine-2,4-piperidin]-1-yl]-5-(2,3-dichlorophenyl)pyrimidine-4-carboxamide,(4M)-6-amino-2-[(3R)-3-amino-3H-spiro[furo[2,3-b]pyridine-2,4-piperidin]-1-yl]-5-(2,3-dichlorophenyl)pyrimidine-4-carboxamide;(4M)-6-amino-2-[(3S)-3-amino-3H-spiro[furo[2,3-b]pyridine-2,4-piperidin]-1-yl]-5-(2,3-dichlorophenyl)pyrimidine-4-carboxamideStep 1:6-amino-2-[3-amino-3H-spiro[furo[2,3-b]pyridine-2,4-piperidin]-1-yl]-5-(2,3-dichlorophenyl)pyrimidine-4-carbonitrile

A solution of DIEA (1.06 mL, 6.13 mmol, 2.00 equiv),6-amino-5-(2,3-dichlorophenyl)-2-methanesulfonylpyrimidine-4-carbonitrile(intermediate 4, 1.04 g, 3.06 mmol) and3H-spiro[furo[2,3-b]pyridine-2,4-piperidin]-3-amine (0.84 g, 3.89 mmol)in EtOH (12 mL) was stirred for 4 h at 60° C. The resulting mixture wasconcentrated under vacuum and purified by flash chromatography on silica(PE:EtOAc, 1:9) to afford the title compound as a yellow solid (900 mg,47% yield). LC/MS (M+1): 468.

Step 2:6-amino-2-[3-amino-3H-spiro[furo[2,3-b]pyridine-2,4-piperidin]-1-yl]-5-(2,3-dichlorophenyl)pyrimidine-4-carboxamide

The title compound was obtained following a similar procedure asdescribed for compounds 124-127, step2, but starting from6-amino-2-[3-amino-3H-spiro[furo[2,3-b]pyridine-2,4-piperidin]-1-yl]-5-(2,3-dichlorophenyl)pyrimidine-4-carbonitrile(0.90 g, 1.47 mmol) as an off-white solid (600 mg, 83%). LC/MS (M+1);486.

Step 3: Isomers Separation

A first separation by preparative HPLC (Column: CHIRALPAK IA, 3×25 cm, 5um; MTBE+10 mM NH₃-MEOH):EtOH, 15%) afforded three fractions:

First elutinq fraction: 150 mg of a mixture of two isomers.

Second elutinq fraction (128): white solid, 68 mg, RT=7.22 min, ¹H NMR(400 MHz, DMSO-d6): 8.00 (dd, J=4.8, 1.2 Hz, 1H), 7.78 (s, 1H), 7.71 (d,J=6.8 Hz, 1H), 7.52 (dd, J=8.0, 1.2 Hz, 1H), 7.29 (t, J=7.6 Hz, 1H),7.18 (s, 1H), 7.12 (dd, J=7.6, 1.6 Hz, 1H), 6.91 (dd, J=7.2, 5.2 Hz,1H), 6.17 (br s, 2H), 4.58-4.52 (m, 2H), 4.13 (s, 1H), 3.40-3.31 (m,2H), 2.32 (brs, 2H), 1.95-1.85 (m, 1H), 1.79-1.72 (m, 3H). RT(analytical column−chiral pack IA, MtBE+0.1% DEA:EtOH=85:15)=1.98 min;purity: 95.1%.

Third elutinq fraction (129): white solid, 62 mg, RT=9.57 min, ¹H NMR(400 MHz, DMSO-d6) δ8.00 (dd, J=4.8, 1.2 Hz, 1H), 7.78 (s, 1H), 7.70 (d,J=6.8 Hz, 1H), 7.52 (dd, J=8.0, 1.2 Hz, 1H), 7.29 (t, J=8.0 Hz, 1H),7.18 (s, 1H), 7.12 (dd, J=7.6, 1.6 Hz, 1H), 6.91 (dd, J=7.2, 5.2 Hz,1H), 6.17 (brs, 2H), 4.58-4.51 (m, 2H), 4.12 (s, 1H), 3.40-3.31 (m, 2H),2.32 (brs, 1H), 1.95-1.85 (m, 1H), 1.79-1.72 (m, 3H). RT (analyticalcolumn−chiral pack IA, MtBE+0.1% DEA:EtOH=85:15)=2.45 min; purity:92.7%.

The isomers from first eluting fraction were separated by preparativeHPLC (CHIRALPAK IA, 3×25 cm, 5 um: Hex: DCM=3:1+10 mM NH₃-MEOH): EtOH,15%).

First elutinq isomer (130): white solid, 46 mg, RT=7.22 min, ¹H NMR (400MHz, DMSO-d6) δ7.99 (d, J=5.6 Hz, 1H), 7.78 (s, 1H), 7.70 (d, J=6.8 Hz,1H), 7.52 (dd, J=8.0, 1.6 Hz, 1H), 7.29 (t, J=8.0 Hz, 1H), 7.18 (s, 1H),7.11 (dd, J=7.0, 1.6 Hz, 1H), 6.90 (dd, J=7.2, 5.2 Hz, 1H), 6.17 (br s,1H), 4.62-4.51 (m, 2H), 4.12 (s, 1H), 3.39-3.31 (m, 2H), 1.95-1.86 (m,1H), 1.79-1.74 (m, 3H). RT=2.81 min (analytical column−chiral pack IA,Hex:DCM=3:1+0.1% DEA:EtOH=85:15); purity: 92.3%.

Second elutinq isomer (131): white solid, 39 mg, Rt=13.8 min, ¹H NMR(400 MHz, DMSO-d6): 7.99 (d, J=3.6 Hz, 1H), 7.78 (s, 1H), 7.70 (d, J=7.6Hz, 1H), 7.52 (dd, J=8.0, 1.2 Hz, 1H), 7.29 (t, J=8.0 Hz, 1H), 7.18 (s,1H), 7.11 (d, J=7.6, 1H), 6.90 (dd, J=7.2, 5.2 Hz, 1H), 6.17 (brs, 1H),4.62-4.51 (m, 2H), 4.11 (s, 1H), 3.35-3.31 (m, 2H), 2.10 (brs, 1H),1.95-1.86 (m, 1H), 1.78-1.71 (m, 3H). RT=2.42 min (analyticalcolumn−chiral pack IA, Hex:DCM=3:1+0.1% DEA:EtOH=85:15); purity: 99.9%.

Compounds from table 3 have been prepared following similar syntheticroutes as the ones described above:

TABLE 3 Compound Analytic description 28 white solid; 1H NMR (400 MHz,DMSO-d6) δ: 7.84 (s, 2H), 7.59 (dd, J = 8.1, 1.6 Hz, 2H), 7.41 (s, 4H),7.36 (t, J = 7.8 Hz, 2H), 7.23 (d, J = 7.5 Hz, 3H), 4.27 (s, 2H), 3.87(s, 1H), 3.12 (s, 2H), 2.68 (s, 1H), 1.98 (s, 9H), 1.89-1.80 (m, 1H),1.72 (s, 0H), 1.68 (s, 6H), 1.56 (d, J = 11.3 Hz, 5H), 1.26 (d, J = 14.2Hz, 2H), 1.10 (dd, J = 25.8, 13.0 Hz, 1H); LC/MS: [M + 1]: 394.2 29white amorphous solid; 1H NMR (400 MHz, DMSO-d6) δ 7.73-7.67 (m, 1H),7.50 (d, J = 8.0 Hz, 1H), 7.28 (t, J = 7.8 Hz, 1H), 7.16-7.08 (m, 2H),6.04 (s, 2H), 4.57 (s, 1H), 4.26 (d, J = 13.0 Hz, 2H), 3.38-3.34 (m,2H), 3.18-3.12 (m, 2H), 1.53-1.40 (m, 2H), 1.36 (s, 2H), 1.26 (d, J =14.1 Hz, 2H). LC/MS: [M + 1]: 411 31 White solid; 1H NMR (300 MHz,DMSO-d6) δ 7.91 (s, 1H), 7.56 (dd, J = 8.0, 1.6 Hz, 1H), 7.40-7.29 (m,2H), 7.18 (dd, J = 7.6, 1.6 Hz, 1H), 4.03 (d, J = 13.4 Hz, 2H), 3.68(dt, J = 13.1, 6.4 Hz, 2H), 1.98 (s, 3H), 1.78 (d, J = 9.2 Hz, 2H), 1.41(d, J = 5.3 Hz, 4H), 1.09 (s, 4H). LC/MS: [M + 1]: 394.0. 32 yellowsolid, 1H NMR (300 MHz, DMSO-d6): 7.90 (s, 1H), 7.59 (dt, J = 8.0, 1.3Hz, 1H), 7.44-7.31 (m, 2H), 7.21 (dd, J = 7.6, 1.6 Hz, 1H), 4.63 (s,1H), 3.06 (d, J = 17.5 Hz, 3H), 2.56 (d, J = 3.8 Hz, 1H), 2.01 (d, J =1.3 Hz, 3H), 1.84 (d, J = 12.5 Hz, 2H), 1.63 (s, 4H), 1.41-1.15 (m, 2H),LC/MS (M + 1): 408.1 33 off-white solid, 1H NMR (300 MHz, DMSO-d6) ?8.08 (s, 0H), 8.02 (s, 2H), 7.54 (dd, J = 8.1, 1.5 Hz, 1H), 7.41-7.26(m, 2H), 7.13 (dd, J = 7.7, 1.5 Hz, 1H), 4.91 (s, 1H), 4.76 (s, 1H),4.37 (s, 8H), 3.90 (dt, J = 11.4, 4.2 Hz, 2H), 3.63 (t, J = 10.4 Hz,2H), 2.18 (dd, J = 13.2, 6.5 Hz, 2H), 1.99 (s, 3H), 1.70 (d, J = 11.7Hz, 2H), LC/MS (M + 1): 422.3 34 orange solid, 1H NMR (400 MHz,Methanol-d4) d 7.54 (d, J = 7.9 Hz, 1H), 7.39-7.29 (m, 1H), 7.20 (d, J =8.2 Hz, 1H), 4.14-3.50 (m, 8H), 3.50-3.20 (m, 4H), 2.86-2.74 (m, 1H),2.22 (s, 2H), 1.36 (s, 2H), LC/MS (M + 1): 423.1 35 white solid; 1H NMR(300 MHz, DMSO-d6) δ 7.88 (s, 1H), 7.59 (dd, J = 8.0, 1.5 Hz, 1H), 7.40(s, 1H), 7.35 (t, J = 7.8 Hz, 1H), 7.23-7.17 (m, 1H), 3.77-3.70 (m, 1H),3.52 (s, 2H), 3.40 (s, 1H), 2.99 (t, J = 6.5 Hz, 1H), 2.08-2.00 (m, 4H),1.96-1.83 (m, 1H), 1.75-1.67 (m, 2H), 1.61-1.50 (m, 3H), 1.39-1.30 (m,1H), LC/MS: [M + 1]: 420.1. 36 off-white solid; 1H NMR (300 MHz,DMSO-d6) δ 7.79 (s, 1H), 7.57 (dd, J = 8.0, 1.6 Hz, 1H), 7.52 (s, 1H),7.40-7.27 (m, 2H), 7.20 (d, J = 7.5 Hz, 1H), 4.28 (s, 1H), 1.95 (s, 4H),1.63 (q, J = 7.9, 7.4 Hz, 1H), 1.50 (s, 1H), 1.28-1.08 (m, 1H), LC/MS:[M + 1]: 394.2. 37 white solid; 1H NMR (300 MHz, DMSO-d6) δ 7.88 (s,1H), 7.59 (dd, J = 8.0, 1.5 Hz, 1H), 7.41 (s, 1H), 7.35 (t, J = 7.8 Hz,1H), 7.21-7.09 (m, 1H), 3.65-3.61 (m, 2H), 3.53 (s, 1H), 2.97 (t, J =6.7 Hz, 1H), 2.00 (s, 3H), 1.92-1.88 (m, 2H), 1.73-1.64 (m, 4H),1.54-1.50 (m, 2H), 1.37-1.21 (m, 1H). LC/MS: [M + 1]: 420.1. 38Amorphous white solid; 1H NMR (400 MHz, DMSO-d6) δ 7.71 (s, 1H), 7.52(d, J = 7.9 Hz, 1H), 7.29 (t, J = 8.1 Hz, 1H), 7.21-7.05 (m, 2H), 6.08(s, 2H), 4.25 (d, J = 12.8 Hz, 2H), 3.69 (d, J = 10.5 Hz, 2H), 3.58 (d,J = 12.3 Hz, 2H), 2.91 (s, 2H), 2.06 (d, J = 13.9 Hz, 2H), 1.69 (t, J =14.5 Hz, 2H), 1.52 (d, J = 5.9 Hz, 2H), 1.36 (t, J = 12.7 Hz, 1H), 1.16(d, J = 13.2 Hz, 1H), 1.00 (t, J = 12.2 Hz, 1H), LC/MS: [M + 1]: 451 39Amorphous white solid; 1H NMR (400 MHz, DMSO-d6) δ 7.71 (s, 1H), 7.52(d, J = 8.0 Hz, 1H), 7.30 (t, J = 7.8 Hz, 1H), 7.23-7.06 (m, 2H), 6.07(s, 2H), 5.08-4.47 (m, 2H), 3.82 (d, J = 11.0 Hz, 1H), 3.26-2.97 (m,3H), 2.88-2.65 (m, 3H), 2.11 (t, J = 12.1 Hz, 1H), 1.89 (d, J = 12.5 Hz,1H), 1.75-1.39 (m, 6H), 1.39-1.24 (m, 2H), 1.24-1.05 (m, 1H), LC/MS:[M + 1]: 465 40 Amorphous white solid; 1H NMR (400 MHz, DMSO-d6) δ 7.74(s, 1H), 7.54 (d, J = 8.1 Hz, 1H), 7.31 (td, J = 8.1, 2.0 Hz, 1H),7.21-7.09 (m, 2H), 6.12 (s, 2H), 4.01-3.77 (m, 4H), 3.74-3.51 (m, 4H),2.67-2.61 (m, 2H), 1.99-1.87 (m, 2H), 1.55 (s, 4H), 1.51-1.40 (m, 1H),LC/MS: [M + 1]: 451 41 Amorphous white solid; 1H NMR (400 MHz, DMSO-d6)δ 7.70 (s, 1H), 7.51 (d, J = 7.9 Hz, 1H), 7.35-7.23 (m, 1H), 7.21-7.04(m, 2H), 6.04 (s, 2H), 4.18-3.94 (m, 2H), 3.45 (s, 2H), 3.03-2.78 (m,2H), 2.41 (s, 2H), 1.40 (t, J = 11.4 Hz, 2H), 1.25 (d, J = 13.1 Hz, 2H),0.92 (d, J = 9.8 Hz, 3H), LC/MS: [M + 1]: 409.1 42 Yellow solid; 1H NMR(300 MHz, DMSO-d6) δ 8.33 (d, J = 20.3 Hz, 3H), 7.90 (s, 1H), 7.61-7.58(m, 1H), 7.46 (s, 1H), 7.36 (t, J = 7.9 Hz, 1H), 7.22-7.18 (m, 1H),3.79-3.34 (m, 5H), 3.05-3.00 (m, 1H), 2.85-2.79 (m, 1H), 2.11-2.09 (m,1H), 2.02-1.93 (m, 4H), 1.76-1.74 (m, 1H), 1.55-1.51 (m, 1H). LC/MS:[M + 1]: 406.0 43 White solid; 1H NMR (300 MHz, DMSO-d6) δ 8.05-7.65 (m,1H), 7.58 (d, J = 7.9 Hz, 1H), 7.36 (dd, J = 14.3, 6.6 Hz, 2H), 7.23(dd, J = 7.4, 4.5 Hz, 1H), 4.27 (d, J = 116.1 Hz, 2H), 2.65 (dd, J =12.5, 5.1 Hz, 1H), 1.98 (d, J = 5.6 Hz, 4H), 1.90-1.43 (m, 5H), 1.34(dd, J = 11.4, 7.5 Hz, 1H). LC/MS: [M + 1]: 394.1 44 White solid; 1H NMR(300 MHz, DMSO-d6) δ 7.95-7.83 (m, 1H), 7.59 (dd, J = 8.0, 1.6 Hz, 1H),7.45 (s, 1H), 7.35 (t, J = 7.8 Hz, 1H), 7.20 (dd, J = 7.7, 1.6 Hz, 1H),4.29 (ddt, J = 18.7, 10.6, 1.3 Hz, 2H), 4.10 (dd, J = 20.9, 10.6 Hz,2H), 2.96 (s, 1H), 2.89 (s, 1H), 2.01 (s, 3H), 1.73 (s, 2H). LC/MS: [M +1]: 384.1 45 White solid; 1H NMR (300 MHz, DMSO-d6) δ 7.87 (s, 1H), 7.59(dd, J = 8.0, 1.6 Hz, 1H), 7.48-7.30 (m, 2H), 7.23 (s, 1H), 4.03-3.54(m, 4H), 2.01 (s, 4H), 1.84-1.18 (m, 8H), 1.07 (s, 3H), LC/MS: [M + 1]:408.0. 43 White solid; 1H NMR (300 MHz, DMSO-d6) δ 7.80 (s, 1H), 7.60(dd, J = 8.0, 1.6 Hz, 1H), 7.44 (s, 1H), 7.36 (t, J = 7.8 Hz, 1H), 7.20(d, J = 7.5 Hz, 1H), 4.41 (s, 1H), 4.01-3.94 (m, 2H), 3.03-2.89 (m, 2H),2.32-2.29 (m, 1H), 2.23-2.20 (m, 2H), 1.99 (s, 3H). LC/MS: [M + 1]:365.9. 47 White solid; 1H NMR (300 MHz, DMSO-d6) δ 8.19 (s, 4H), 7.59(dd, J = 8.1, 1.5 Hz, 1H), 7.49 (s, 1H), 7.37 (t, J = 7.8 Hz, 1H), 7.21(dd, J = 7.6, 1.5 Hz, 1H), 5.06 (s, 1H), 4.61 (d, J = 13.7 Hz, 1H), 4.01(d, J = 12.0 Hz, 1H), 3.92 (d, J = 10.8 Hz, 1H), 3.59-3.55 (m, 1H), 3.45(t, J = 11.5 Hz, 1H), 3.34-3.22 (m, 3H), 2.05 (s, 3H), LC/MS: [M + 1]:396.0. 48 White solid; 1H NMR (300 MHz, DMSO-d6) δ 8.23 (s, 4H), 7.60(dd, J = 8.1, 1.5 Hz, 1H), 7.50 (s, 1H), 7.36 (t, J = 7.8 Hz, 1H),7.17-7.11 (m, 1H), 4.93 (s, 1H), 4.60 (s, 1H), 4.02 (d, J = 12.0 Hz,1H), 3.92 (d, J = 11.1 Hz, 1H), 3.59 (dd, J = 12.2, 3.2 Hz, 1H), 3.47(d, J = 12.0 Hz, 1H), 3.33-3.21 (m, 3H), 2.05 (s, 3H), LC/MS: [M + 1]:396.0. 49 Amorphous white solid; 1H NMR (400 MHz, DMSO-d6) δ 7.67 (s,1H), 7.52 (d, J = 8.0 Hz, 1H), 7.30 (t, J = 8.1 Hz, 1H), 7.23-7.09 (m,2H), 6.02 (s, 2H), 4.02-3.59 (m, 4H), 3.50 (s, 1H), 1.88 (s, 2H),1.82-1.25 (m, 6H), LC/MS: [M + 1]: 395 50 Amorphous white solid; 1H NMR(400 MHz, DMSO-d6) δ 7.69 (s, 1H), 7.57-7.46 (m, 1H), 7.37-7.24 (m, 1H),7.24-7.03 (m, 2H), 6.01 (s, 2H), 3.67-3.48 (m, 2H), 3.48-3.33 (m, 2H),3.05-2.90 (m, 1H), 2.20-2.05 (m, 1H), 1.83-1.31 (m, 6H), 1.32-0.92 (m,3H), LC/MS: [M + 1]: 421 51 White solid; 1H NMR (400 MHz, DMSO-d6) δ7.72 (s, 1H), 7.51 (dd, J = 8.0, 1.6 Hz, 1H), 7.43-7.14 (m, 7H),7.13-7.06 (m, 1H), 6.06 (s, 2H), 4.23-3.80 (m, 2H), 3.57-3.43 (m, 1H),3.34 (d, J = 28.3 Hz, 2H), 3.17 (q, J = 8.9 Hz, 1H), 2.64 (d, J = 4.1Hz, 1H), 2.38 (s, 1H), 2.23-1.56 (m, 2H), LC/MS: [M + 1]: 457 52 Whiteamorphous solid; LC/MS: [M + 1]: 477. 53 White amorphous solid; 1H NMR(400 MHz, DMSO-d6) δ 7.70 (s, 1H), 7.51 (dd, J = 8.1, 1.6 Hz, 1H), 7.28(t, J = 7.8 Hz, 1H), 7.14 (s, 1H), 7.10 (dd, J = 7.6, 1.6 Hz, 1H), 6.04(s, 2H), 4.25-4.08 (m, 2H), 3.51-3.36 (m, 2H), 1.50-1.08 (m, 10H), 0.89(t, J = 6.6 Hz, 3H), LC/MS: [M + 1]: 423 54 White amorphous solid; 1HNMR (400 MHz, DMSO-d6) δ 7.64 (s, 1H), 7.51 (d, J = 7.9 Hz, 1H), 7.28(t, J = 7.8 Hz, 1H), 7.22-7.05 (m, 2H), 6.17 (s, 2H), 4.91 (s, 1H), 3.87(d, J = 8.7 Hz, 2H), 3.63 (d, J = 8.7 Hz, 2H), 3.07 (s, 2H), 2.55 (s,2H), LC/MS: [M + 1]: 383 55 White amorphous solid; 1H NMR (400 MHz,DMSO-d6) δ 7.63 (s, 1H), 7.53 (d, J = 8.3 Hz, 1H), 7.30 (dd, J = 9.1,6.6 Hz, 1H), 7.18 (s, 1H), 7.13 (t, J = 6.4 Hz, 1H), 6.17 (s, 2H), 3.86(dd, J = 23.9, 8.5 Hz, 2H), 3.57 (t, J = 8.9 Hz, 2H), 3.12 (d, J = 6.0Hz, 2H), 2.67 (s, 2H), 1.25 (s, 3H), LC/MS: [M + 1]: 381 56 Off-whitesolid; 1H NMR (300 MHz, DMSO-d6) δ 7.88 (s, 1H), 7.57 (dd, J = 8.0, 1.6Hz, 1H), 7.42-7.28 (m, 2H), 7.18 (dd, J = 7.6, 1.6 Hz, 1H), 3.74 (dd, J= 11.6, 7.9 Hz, 2H), 3.58-3.47 (m, 2H), 2.93-2.83 (m, 2H), 2.55-2.42 (m,4H), 2.20 (s, 3H), 1.98 (s, 3H), LC/MS: [M + 1]: 406.3. 57 Off-whitesolid; 1H NMR (300 MHz, DMSO-d6) δ 7.82 (s, 1H), 7.58 (dd, J = 8.0, 1.6Hz, 1H), 7.40 (s, 1H), 7.34 (t, J = 7.8 Hz, 1H), 7.18 (dd, J = 7.7, 1.6Hz, 1H), 5.00 (s, 1H), 4.00 (d, J = 8.8 Hz, 2H), 3.72 (d, J = 8.8 Hz,2H), 3.43 (s, 2H), 1.97 (s, 3H), LC/MS: [M + 1]: 382.3 58 Yellow solid;1H NMR (400 MHz, DMSO-d6) δ 8.62 (d, J = 48.3 Hz, 3H), 7.86 (d, J = 47.1Hz, 1H), 7.60 (ddd, J = 8.1, 3.2, 1.5 Hz, 1H), 7.44 (s, 1H), 7.37 (td, J= 7.9, 2.7 Hz, 1H), 7.26-7.17 (m, 1H), 3.74 (d, J = 41.5 Hz, 4H),2.92-2.63 (m, 1H), 2.36-1.86 (m, 5H), 1.09 (p, J = 6.3 Hz, 2H), LC/MS:[M + 1]: 392 60 Yellow solid; 1H NMR (400 MHz, DMSO-d6) δ 8.64 (s, 1H),8.16 (s, 1H), 7.90 (s, 1H), 7.50 (s, 1H), 7.43 (s, 1H), 7.18 (t, J = 7.5Hz, 1H), 4.05 (d, J = 13.0 Hz, 2H), 3.71 (ddd, J = 13.1, 8.0, 5.0 Hz,2H), 1.45 (q, J = 4.9, 4.3 Hz, 4H), 1.12 (s, 3H), LC/MS: [M + 1]: 352 61Yellow solid; 1H NMR (400 MHz, DMSO-d6) δ 8.58 (s, 1H), 8.15 (s, 1H),7.95 (d, J = 9.1 Hz, 1H), 7.64 (dd, J = 9.1, 6.6 Hz, 1H), 7.57 (s, 1H),7.43 (d, J = 6.6 Hz, 1H), 4.08-4.05 (m, 2H), 3.82-3.77 (m, 2H),1.52-1.40 (m, 4H), 1.14 (s, 3H). LC/MS: [M + 1]: 354.2. 62 Yellow oil;1H NMR (400 MHz, Methanol-d4) δ 8.55-8.15 (m, 1H), 7.75-7.73 (m, 1H),7.02-7.00 (m, 1H), 4.01-3.71 (m, 6H), 1.72-1.61 (m, 4H), 1.41-1.21 (m,7H), 0.93-0.78 (m, 1H). LC/MS: [M + 1]: 401.0. 64 White amorphous solid;1H NMR (400 MHz, DMSO-d6 + D2O) δ 7.50 (dd, J = 8.1, 1.5 Hz, 1H), 7.29(t, J = 7.9 Hz, 1H), 7.10 (dd, J = 7.7, 1.6 Hz, 1H), 4.70 (d, J = 50.7Hz, 1H), 4.20-3.85 (m, 1H), 3.20-2.84 (m, 2H), 2.81-2.56 (m, 2H),1.76-1.47 (m, 2H), LC/MS: [M + 1]: 399 65 White amorphous solid; 1H NMR(400 MHz, DMSO-d6) δ 7.64 (s, 1H), 7.51 (d, J = 8.0 Hz, 1H), 7.29 (t, J= 7.9 Hz, 1H), 7.21-7.06 (m, 2H), 6.21 (s, 1H), 6.00 (s, 2H), 3.92 (s,1H), 3.01 (d, J = 4.1 Hz, 1H), 1.59 (dt, J = 33.1, 11.9 Hz, 6H), 1.29(d, J = 9.0 Hz, 2H), LC/MS: [M + 1]: 395 68 White solid; 1H NMR (300MHz, DMSO-d6) δ 7.87 (s, 1H), 7.58 (dd, J = 8.0, 1.6 Hz, 1H), 7.44-7.30(m, 2H), 7.22 (d, J = 21.9 Hz, 1H), 4.56 (d, J = 13.4 Hz, 1H), 4.18 (d,J = 14.8 Hz, 1H), 3.65-3.43 (m, 3H), 3.13 (s, 1H), 2.91 (s, 1H), 1.99(s, 3H), 1.94-1.67 (m, 3H), 1.63-1.59 (m, 2H), 1.22-1.12 (t, J = 14.9Hz, 1H), LC/MS: [M + 1]: 406.1. 69 White amorphous solid; 1H NMR (400MHz, DMSO-d6) δ 7.63 (s, 1H), 7.52 (ddd, J = 8.0, 3.2, 1.6 Hz, 1H), 7.29(td, J = 7.9, 2.2 Hz, 1H), 7.18 (d, J = 10.6 Hz, 1H), 7.10 (dt, J = 7.6,2.0 Hz, 1H), 6.18 (s, 2H), 4.34 (q, J = 6.7 Hz, 1H), 4.21 ? 4.08 (m,2H), 3.74 (ddd, J = 14.7, 7.8, 3.6 Hz, 2H), 3.63 (dd, J = 8.7, 5.6 Hz,2H), LC/MS: [M + 1]: 353 70 White amorphous solid; 1H NMR (400 MHz,DMSO-d6) δ 7.67 (s, 1H), 7.51 (dd, J = 8.1, 1.6 Hz, 1H), 7.28 (t, J =7.9 Hz, 1H), 7.16 (s, 1H), 7.09 (dd, J = 7.6, 1.5 Hz, 1H), 6.08 (s, 2H),3.84 (d, J = 11.2 Hz, 2H), 3.41 (d, J = 10.6 Hz, 3H), 2.61 (d, J = 6.9Hz, 2H), 1.58 (s, 2H), 0.78 ? 0.68 (m, 1H), LC/MS: [M + 1]: 393 71 Whiteamorphous solid; 1H NMR (400 MHz, DMSO-d6) δ 7.67 (s, 1H), 7.50 (d, J =8.1 Hz, 1H), 7.28 (t, J = 7.9 Hz, 1H), 7.15 (s, 1H), 7.09 (d, J = 7.6Hz, 1H), 6.01 (s, 2H), 3.60 (s, 2H), 3.50 (s, 2H), 3.16 (d, J = 10.3 Hz,1H), 2.54 (s, 2H), 2.00 (dt, J = 12.6, 6.5 Hz, 1H), 1.65 (dd, J = 12.6,6.4 Hz, 1H), LC/MS: [M + 1]: 367 72 White solid; 1H NMR (300 MHz,DMSO-d6) δ 7.88 (s, 1H), 7.59 (dd, J = 8.0, 1.5 Hz, 1H), 7.45-7.31 (m,2H), 7.20 (dd, J = 7.6, 1.6 Hz, 1H), 3.80-3.67 (m, 2H), 3.60-3.42 (m,3H), 2.74 (s, 2H), 2.00 (s, 3H), 1.90-1.69 (m, 2H), 1.55-1.39 (m, 2H),LC/MS: [M + 1]: 406.1. 73 White solid; 1H NMR (300 MHz, DMSO-d6) δ 7.88(s, 1H), 7.59 (dd, J = 8.0, 1.6 Hz, 1H), 7.46-7.31 (m, 2H), 7.20 (dd, J= 7.6, 1.6 Hz, 1H), 3.81-3.69 (m, 2H), 3.56-3.44 (m, 3H), 2.79-2.66 (m,2H), 2.00 (s, 3H), 1.89-1.70 (m, 2H), 1.53-1.39 (m, 2H), LC/MS: [M + 1]:406.1. 74 White solid; 1H NMR (300 MHz, DMSO-d6) δ 7.88 (s, 1H), 7.59(dd, J = 8.0, 1.6 Hz, 1H), 7.46-7.32 (m, 2H), 7.20 (dd, J = 7.7, 1.6 Hz,1H), 3.81-3.67 (m, 2H), 3.61-3.44 (m, 3H), 2.83-2.68 (m, 2H), 2.00 (s,3H), 1.89-1.70 (m, 2H), 1.59-1.38 (m, 2H), LC/MS: [M + 1]: 406.1. 75White solid; 1H NMR (300 MHz, DMSO-d6) δ 7.88 (s, 1H), 7.59 (dd, J =8.1, 1.6 Hz, 1H), 7.45-7.31 (m, 2H), 7.20 (dd, J = 7.7, 1.5 Hz, 1H),3.78-3.59 (m, 3H), 3.46-3.44 (m, 1H), 3.05-3.03 (m, 1H), 2.89-2.78 (m,1H), 2.40-2.31 (m, 1H), 2.07-1.86 (s, 5H), 1.42-1.39 (m, 2H), LC/MS:[M + 1]: 406.1. 76 White solid; 1H NMR (300 MHz, DMSO-d6) δ 7.88 (s,1H), 7.59 (dd, J = 8.0, 1.6 Hz, 1H), 7.45-7.30 (m, 2H), 7.20 (dd, J =7.6, 1.6 Hz, 1H), 3.79-3.57 (m, 3H), 3.51-3.38 (m, 1H), 3.06-3.01 (m,1H), 2.88-2.79 (m, 1H), 2.38-2.27 (m, 1H), 2.08-2.00 (m, 4H), 1.95-1.83(m, 1H), 1.50-1.31 (m, 2H), LC/MS: [M + 1]: 406.1. 77 White solid; 1HNMR (300 MHz, DMSO-d6) δ 7.90 (s, 1H), 7.60 (dd, J = 8.0, 1.6 Hz, 1H),7.46-7.33 (m, 2H), 7.21 (dd, J = 7.6, 1.6 Hz, 1H), 3.80-3.59 (m, 3H),3.49-3.42 (m, 1H), 3.10-3.02 (m, 1H), 2.91-2.81 (m, 1H), 2.42-2.32 (m,1H), 2.11-1.87 (m, 6H), 1.51-1.35 (m, 2H), LC/MS: [M + 1]: 406.1. 78White solid; 1H NMR (300 MHz, DMSO-d6) δ 8.06 (s, 1H), 7.60 (dd, J =8.1, 1.6 Hz, 1H), 7.55 (s, 1H), 7.35 (t, J = 7.8 Hz, 1H), 7.23 (dd, J =7.6, 1.6 Hz, 1H), 4.09-3.82 (m, 4H), 1.51 (brs, 4H), 1.21 (s, 3H),LC/MS: [M + 1]: 414.0 79 White solid; 1H NMR (300 MHz, DMSO-d6) δ 8.03(s, 1H), 7.60-7.58 (m, 1H), 7.52 (s, 1H), 7.35 (t, J = 7.9 Hz, 1H),7.24-7.22(m, 1H), 4.03 (brs, 2H), 3.66 (brs, 2H), 1.43-1.41 (m, 4H),1.09 (s, 3H), LC/MS: [M + 1]: 414.3 80 White solid; 1H NMR (300 MHz,DMSO-d6) δ 7.85 (s, 1H), 7.57 (dd, J = 8.1, 1.6 Hz, 1H), 7.43-7.30 (m,2H), 7.18 (d, J = 7.6 Hz, 1H), 5.06 (s, 1H), 3.91 (s, 1H), 3.82-3.60 (m,2H), 3.48-3.35 (m, 3H), 2.16-1.99 (m, 5H), LC/MS: [M + 1]: 382.0 81Off-White solid; 1H NMR (400 MHz, Methanol-d4) δ 8.29 (d, J = 4.9 Hz,1H), 7.25 (d, J = 4.9 Hz, 1H), 4.15 (s, 1H), 4.20-4.10 (m, 2H), 3.86(ddd, J = 13.2, 7.8, 4.1 Hz, 2H), 2.11 (s, 3H), 1.65 (tdd, J = 13.1,10.4, 4.2 Hz, 4H), 1.30 (s, 3H), LC/MS: [M + 1]: 395.0 82 White solid;1H NMR (400 MHz, DMSO-d6) δ 7.91 (s, 1H), 7.48 (dd, J = 8.9, 2.5 Hz,1H), 7.37 (s, 1H), 7.32-7.19 (m, 2H), 3.99-3.77 (m, 4H), 2.01 (s, 3H),1.50 (t, J = 5.8 Hz, 4H), 1.17 (s, 3H), LC/MS: [M + 1]: 378.0 83Off-White solid; 1H NMR (400 MHz, Methanol-d4) δ 8.60 (s, 1H), 8.46 (d,J = 5.0 Hz, 1H), 7.30 (d, J = 4.9 Hz, 1H), 4.12 (ddd, J = 13.8, 7.2, 4.2Hz, 2H), 3.88 (ddd, J = 13.8, 7.7, 4.1 Hz, 2H), 2.11 (s, 3H), 1.64 (th,J = 13.0, 4.2 Hz, 4H), 1.28 (s, 3H), LC/MS: [M + 1]: 361.0 84 Whitesolid; 1H NMR (300 MHz, DMSO-d6) δ 7.85 (s, 1H), 7.57 (dd, J = 8.1, 1.6Hz, 1H), 7.43-7.29 (m, 2H), 7.17 (d, J = 7.6 Hz, 1H), 5.08 (s, 1H), 4.03(s, 1H), 3.84-3.54 (m, 3H), 3.43-3.35 (m, 1H), 3.22-3.09 (m, 1H),2.17-1.98 (s, 4H), LC/MS: [M + 1]: 382.0 86 Yellow solid; 1H NMR (300MHz, DMSO-d6) δ 8.56-8.48 (m, 2H), 7.88 (s, 1H), 7.41 (s, 1H), 7.25-7.17(m, 2H), 4.00 (d, J = 13.2 Hz, 2H), 3.66 (dt, J = 12.9, 6.3 Hz, 2H),2.09 (s, 4H), 1.39 (d, J = 5.6 Hz, 4H), 1.08 (s, 3H), LC/MS: [M + 1]:327.2 87 LC/MS: [M + 1]: 394.1. 88 White solid; 1H NMR (400 MHz,DMSO-d6) 7.81-7.73(m, 1H), 7.58 (dd, J = 8.1, 1.6 Hz, 1H), 7.40-7.30 (m,3H), 7.22 (d, J = 7.6 Hz, 1H), 3.88 (brs, 1H), 2.75 (s, 1H), 2.05-1.96(m, 4H), 1.86-1.77 (m, 1H), 1.74-1.69 (m, 2H), 1.34-1.23 (m, 2H),1.08-0.83 (m, 1H). LC/MS: [M + 1]: 394.0. 89 White solid; 1H NMR (300MHz, Methanol-d4) δ 7.50 (dd, J = 8.1, 1.6 Hz, 1H), 7.29 (t, J = 7.9 Hz,1H), 7.14 (dd, J = 7.7, 1.6 Hz, 1H), 4.03-3.89 (m, 1H), 3.00-2.93 (m,1H), 2.68 (s, 1H), 2.46 (s, 2H), 2.45-2.33 (m, 1H), 2.06 (s, 4H),2.00-1.83 (m, 2H), 1.55-1.40 (m, 1H), 1.31-1.16 (m, 4H), LC/MS: [M + 1]:394.0. 90 White solid; 1H NMR (300 MHz, Methanol-d4) δ 7.50 (dd, J =8.1, 1.6 Hz, 1H), 7.29 (t, J = 7.9 Hz, 1H), 7.14 (dd, J = 7.7, 1.6 Hz,1H), 4.03-3.89 (m, 1H), 3.00-2.93 (m, 1H), 2.68 (s, 1H), 2.46 (s, 2H),2.45-2.33 (m, 1H), 2.06 (s, 4H), 2.00-1.83 (m, 2H), 1.55-1.40 (m, 1H),1.31-1.16 (m, 4H), LC/MS: [M + 1]: 394.0. 91 White solid; 1H NMR (300MHz, Methanol-d4) δ 7.50 (dd, J = 8.1, 1.6 Hz, 1H), 7.29 (t, J = 7.9 Hz,1H), 7.14 (dd, J = 7.7, 1.6 Hz, 1H), 4.03-3.89 (m, 1H), 3.00-2.93 (m,1H), 2.68 (s, 1H), 2.46 (s, 2H), 2.45-2.33 (m, 1H), 2.06 (s, 4H),2.00-1.83 (m, 2H), 1.55-1.40 (m, 1H), 1.31-1.16 (m, 4H), LC/MS: [M + 1]:394.0. 92 White solid; 1H NMR (300 MHz, DMSO-d6) δ 7.65 (s, 1H), 7.49(dd, J = 8.1, 1.6 Hz, 1H), 7.38-7.21 (m, 2H), 7.19-7.05 (m, 1H), 6.01(s, 2H), 3.76 (s, 2H), 3.59 (s, 2H), 1.91 (s, 1H), 1.57-1.33 (m, 7H),1.03 (d, J = 12.8 Hz, 3H), LC/MS: [M + 1]: 409.1 93 White solid; 1H NMR(300 MHz, DMSO-d6) δ 7.77 (s, 1H), 7.57 (d, J = 8.1 Hz, 1H), 7.40-7.28(m, 2H), 7.21 (d, J = 6.6 Hz, 2H), 4.00-3.86 (m, 1H), 2.85-2.78 (s, 1H),1.96 (s, 3H), 1.83-1.67 (m, 2H), 1.58-1.44 (m, 6H), LC/MS: [M + 1]: 394106 Yellow powder; 1H NMR (400 MHz, Methanol-d4) δ 7.53 (dd, J = 8.1,1.5 Hz, 1H), 7.33 (t, J = 7.8 Hz, 1H), 7.20 (dd, J = 7.6, 1.5 Hz, 1H),5.63 (t, J = 56.9 Hz, 1H), 4.61 (dt, J = 13.7, 3.9 Hz, 2H), 1.76 (td, J= 12.8, 4.7 Hz, 2H), 1.55 (d, J = 13.5 Hz, 2H), 1.43-0.73 (m, 2H),LC/MS: [M + 1]: 431 107 Yellow powder; 1H NMR (400 MHz, Methanol-d4) δ7.53 (dd, J = 8.1, 1.6 Hz, 1H), 7.33 (t, J = 7.8 Hz, 1H), 7.20 (dd, J =7.6, 1.5 Hz, 1H), 5.64 (t, J = 56.9 Hz, 1H), 4.62 (dt, J = 13.6, 4.0 Hz,2H), 1.76 (ddd, J = 13.5, 11.9, 4.7 Hz, 2H), 1.60-1.45 (m, 2H),1.41-0.76 (m, 2H), LC/MS: [M + 1]: 431 108 Off-white solid; 1H NMR (400MHz, Methanol-d4) δ 7.50 (dd, J = 8.1, 1.6 Hz, 1H), 7.30 (t, J = 7.8 Hz,1H), 7.16 (dd, J = 7.6, 1.6 Hz, 1H), 3.93-3.68 (m, 4H), 1.98-1.78 (m,4H), 1.65 (t, J = 6.0 Hz, 2H), 1.21 (s, 3H), LC/MS: [M + 1]: 409.2. 109Off-white solid; 1H NMR (400 MHz, Methanol-d4) δ7.50 (dd, J = 8.1, 1.6Hz, 1H), 7.30 (t, J = 7.8 Hz, 1H), 7.16 (dd, J = 7.6, 1.6 Hz, 1H),3.93-3.68 (m, 4H), 1.98-1.78 (m, 4H), 1.65 (t, J = 6.0 Hz, 2H), 1.21 (s,3H), LC/MS: [M + 1]: 409.2. 110 Off-white solid; 1H NMR (400 MHz,Methanol-d4) δ 7.50 (dd, J = 8.1, 1.6 Hz, 1H), 7.30 (t, J = 7.8 Hz, 1H),7.16 (dd, J = 7.6, 1.6 Hz, 1H), 3.93-3.68 (m, 4H), 1.98-1.78 (m, 4H),1.65 (t, J = 6.0 Hz, 2H), 1.21 (s, 3H), LC/MS: [M + 1]:409.2. 111Off-white solid; 1H NMR (400 MHz, Methanol-d4) δ 7.50 (dd, J = 8.1, 1.6Hz, 1H), 7.30 (t, J = 7.8 Hz, 1H), 7.16 (dd, J = 7.6, 1.6 Hz, 1H),3.93-3.68 (m, 4H), 1.98-1.78 (m, 4H), 1.65 (t, J = 6.0 Hz, 2H), 1.21 (s,3H), LC/MS: [M + 1]: 428.2 112 White solid; 1H NMR (300 MHz, DMSO-d6) δ7.68 (s, 1H), 7.49 (dd, J = 8.1, 1.5 Hz, 1H), 7.27 (t, J = 7.8 Hz, 1H),7.15 (s, 1H), 7.08 (dd, J = 7.7, 1.6 Hz, 1H), 6.01 (s, 1H), 4.54 (d, J =11.6 Hz, 1H), 3.70-3.48(m, 1H), 3.09 (brs, 1H), 2.98 (s, 3H), 2.52 (s,1H), 1.95 (d, J = 11.3 Hz, 2H), 1.59 (d, J = 14.7 Hz, 4H), 1.31 (d, J =13.1 Hz, 2H), LC/MS: [M + 1]: 409.1 115 White solid; 1H NMR (400 MHz,Chloroform-d) δ 7.51 (s, 1H), 7.06-6.95 (m, 1H), 6.83-6.74 (m, 1H),5.41-5.35 (m, 1H), 4.12-3.95 (m, 4H), 3.92-3.76 (m, 2H), 2.13 (s, 3H),1.74-1.53 (m, 4H), 1.28 (s, 5H), LC/MS: [M + 1]: 408.1. 116 White solid;1H NMR (400 MHz, Chloroform-d) δ 7.52 (s, 1H), 7.06-6.94 (m, 1H),6.83-6.74 (m, 1H), 5.58 (s, 1H), 4.07-3.88 (m, 6H), 2.13 (s, 3H),1.77-1.62 (m, 4H), 1.30-1.28 (m, 5H), LC/MS: [M + 1]: 408.1.

Example 3: Testing Compounds of the Present Invention for InhibitoryActivities Against SHP2 and ERK1 2

SHP2 biochemical assay:

The inhibition of SHP2 by compounds of the invention was monitored usingthe surrogate substrate DiFMUP after protein activation by a peptidebearing two appropriately spaced phosphotyrosine. Full length SHP2protein (Recombinant HumanSHP-2, E. coli derived Ser2Arg593, N-terminal6His tag from R&D systems; 0.0.24 nM) was incubated with activatingpeptide, IRSI_2pY (New England Peptide, 140 nM) and DiFMUP (molecularprobes, 80 uM) at RT in buffer (HEPES pH 7.2 60 mM, DDT 5 mM, KCl 75 mM,NaCl 75 mM, EDTA 1 mM, Tween 20 0.05%) in presence of compound (10concentrations range, top concentration 50 μM) for 60 min. Thegeneration of the DiFMU product by activated SHP2 was monitored throughFluorescence measurement with a PerkinElmer Envision reader. Theinhibitor dose response curves were analyzed with Genedata Screener.IC₅₀ ranges for compounds of the invention are shown in table 4 below.

p-Erk Cellular assay in MDA-MB-468 and KYSE520:

The effect of SHP2 inhibitors on pERK level was assessed usingphospho-specific antibody using Mesoscale quantification platform. Formeasuring change in pERK levels using mesoscale, 30,000 cells of MDAMB468 and KYSE520 cells were plated in 96-well tissue culture treatedplate in 175 ul volume of media. After an overnight incubation at 37°C., various SHP2 inhibitors were added in different concentration toeach well maintaining duplicate wells across plates and incubated withcompounds for 2 h at 37° C. followed by a wash with ice cold PBS buffer.The cells were then lysed in lysis buffer and processed and analyzed forp-ERK/ERK as per manufacturer's instructions (Mesoscale discovery, catNo. K15107D-3). IC₅₀ ranges for compounds of the invention are shown intable 4 below.

TABLE 4 SHP-2 Biochemical pERK1/2 pERK1/2 assay in KYSE520 in MDA-MB-468Compound IC₅₀ (uM) IC₅₀ (uM) IC₅₀ (uM) 1 3.700 NT 12    2 2.100 NT 3.0853 0.160 0.754 0.346 4 3.700 NT NT 5 0.072 1.094 1.009 6 2.700 NT NT 70.120 1.373 0.606 8 0.200 1.512 2.184 9 1.100 6.437 1.497 10 9.600 NT NT11 0.590 10.223  1.833 12 1.600 NT NT 13 >10 NT NT 14 8.800 NT NT 15 NDNT NT 16 0.060 1.140 0.516 17 12.000 NT NT 18 0.104 2.396 0.231 1987.000 NT NT 20 0.150 8.452 0.492 21 1.600 NT NT 22 21.000 NT NT 234.700 NT NT 24 0.270 7.646 2.347 25 >10 NT NT 26 >10 >10     8.185 270.082 1.467 0.342 28 0.360 11.489  1.631 29 0.260 7.700 1.166 30 0.110NT 0.475 31 7.900 NT NT 32 0.200 3.608 0.736 33 2.400 NT NT 34 1.100 NTNT 35 1.100 NT NT 36 13.000 NT NT 37 1.100 NT NT 38 7.600 NT NT 39 6.300NT NT 40 3.900 NT NT 41 0.310 2.993 0.908 42 4.800 NT NT 43 3.100 NT NT44 11.000 NT NT 45 0.170 2.098 0.646 46 5.500 NT NT 47 >10 NT NT 48 >10NT NT 49 0.120 2.538 0.683 50 10.000 NT NT 51 1.500 NT NT 52 >10 NT NT53 0.200 1.300 0.652 54 7.700 NT NT 55 1.700 NT NT 56 0.960 NT NT 57 >10NT NT 58 4.400 NT NT 60 >10 NT NT 61 >10 NT NT 62 >10 NT NT 64 10.000 NTNT 65 3.700 NT NT 66 0.052 0.863 0.503 67 16.000 NT NT 68 6.200 NT NT 695.600 NT NT 70 5.300 NT NT 71 1.300 NT NT 72 6.700 NT NT 73 5.200 NT NT74 >10 NT NT 75 2.100 NT NT 76 1.000 NT NT 77 >10 NT NT 78 1.400 NT NT79 0.030 0.837 0.177 80 5.300 NT NT 81 0.720 11.345  1.715 82 2.000 NTNT 83 14.000 NT NT 84 6.300 NT NT 85 0.048 1.241 0.407 86 >10 NT NT 871.200 NT NT 88 0.410 4.250 NT 89 13.000 NT NT 90 >10 NT NT 91 0.1002.600 NT 93 2.3 NT NT 94 2.600 NT NT 95 0.022 0.486 0.497 96 0.062 0.993NT 97 4.400 NT 98 0.049 1.2  0.395 99 3.7 NT NT 100 0.5 12.8   101 0.0750.390 0.445 102 17.000 NT NT 103 5.600 NT NT 104 0.120 2.249 NT 10510.000 NT NT 106 15.000 NT NT 107 3.200 NT NT 108 1.300 NT NT 109 0.0710.468 0.42  110 4.400 NT NT 111 0.530 4.700 NT 112 0.066 0.596 0.67  1130.660 NT NT 114 0.045 0.284 0.316 115 0.570 NT NT 116 >10 NT NT 1170.001 0.001 NT 118 0.041 0.114 NT 119 0.001 0.021 NT 120 0.270 NT NT 1210.002 0.016 NT 122 0.017 0.048 NT 123 0.015 0.058 NT 124 0.006 0.268 NT125 0.530 NT NT 126 1.200 NT NT 127 >10 NT NT 128 0.006 0.161 NT 1290.330 NT NT 130 0.077 2.245 NT 131 7.000 NT NT

Example 4: In-Vitro Safety Profile—Testing the Selectivity Over hErg

Inhibition of the ion channel hErg (or Kv11.1) current causes QTinterval prolongation resulting in potentially fatal ventriculartachyarrhythmia called Torsade de Pointes. This is one of the majorcauses of cardiotoxicity and hErg channel activity is usually evaluatedearly in the drug development process to mitigate cardiotoxicity risk.

hERG ion channel activity was assessed using a patch clamp technique instable Kv11.1 (hERG) transfected human embryonic kidney cell line(HEK293). Whole cell recordings were carried out with an automated patchclamp device Patchliner™ from Nanion Technologies, Munich followingmanufacturer recommendation. Different concentrations of the testcompound or reference, quinidine, were applied to whole cells suspensionand current was measured using a pulse pattern with fixed amplitudes.The effect on Kv11.1 (hERG) ion channel activity was judged from thetail current amplitude and Changes in Kv11.1 (hERG) ion channel activitybetween control value (defined as 100%) and test compound and reportedas percent change of control value of COI.

TABLE 5 In-vitro safety profile Split between hErg and cell activity Ki(patch Clamp)/ Structure No. IC50 (KYSE)

SHP-099 (example 7 of WO2015/107493) 2.5

Compound No. 3 > 14

RMC-4550 (example 228 of WO2018/013597) 26

Compound No. 5 >10

Compound 117 >50

Compound 119 97

Compound 121 >600

Compound 122 >50

Compound 123 >100

Result

The compounds of the present invention show a much better split betweenhErg activity (Ki in patch clamp assay) and cell activity (IC50 in KYSE)as compared to known SHP2 inhibitors SHP-099 and RMC-4550. This shouldtranslate to less likelihood of cardio toxicity when administered tosubjects.

Example 5: Testing the Pharmacokinetic Properties of the Compounds ofthe Present Invention in Mouse

Female CD1 mice (N=3) received a single oral (gavage) or a singleintravenous (bolus) injection of compound. Dosing vehicles weretypically given by oral gavage as 0.5% Methocel K4M/0.25% Tween20 insodium citrate buffer, 0.1M, pH 3.0 or, for IV administration, as asolution in 10% Kolliphor HS15 in Na acetate buffer, 0.01M, pH 4.5.Consecutive blood samples were taken sub-lingually under isofluoraneinhalation from animals after 0.083 (IV), 0.25, 0.5, 1, 2, 4, 6 and 24 hand were further processed to obtain plasma. Samples were proteinprecipitated and analyzed by LC/MS/MS.

TABLE 6 PK data in mouse Cmax AUC ng/ml*h ng/mL Clearance (normalized Vdss Normalized Name, No. L/h/kg 1 mpk) (L/kg) to 1 mgk) SHP-099 5.7 129 548 Compound 27 2.24 230 8.7 48 Compound 95 0.77 1214 3.99 150

Result

In mouse PK, the compounds of the present invention (No. 27 and 95)shows a lower clearance and higher exposure as compared to the referencecompound SHP-099.

Example 6: Testing Compounds of the Present Invention for InhibitoryActivities Against SHP2 Active Mutant E76K with and without anActivating Peptide

A selection of compounds has been tested in a biochemical assay usingsame conditions as described in example 3, but with an auto-activatedmutant protein SHP2 E76K with and without the addition of the activatingpeptide IRSI_2pY (New England Peptide, 140 nM).

TABLE 7 SHP-2 SHP-2 E76Z SHP-2 E76Z IC₅₀ (μM) IC₅₀ (μM) IC₅₀ (μM)Compound peptide No peptide peptide SHP-099 47 nM 34 uM * 250 uM *(example 7 of (+10 uM WO2015/107493) ppIRS-1) Compound 117 0.4 nM 0.5 nM1.1 nM * From LaRochelle J. R. et al., Nature comm., 2018, 9: 4508, 1-10

In strongly SHP2 activating conditions, our compound retains a nM rangepotency while known inhibitor SHP099 losses several logs in similarconditions. This can be an advantage for treating cancer with stronglyactivating SHP2 mutations.

Example 6: Activity in U937 Cells

Selected compounds were tested in a cytokine release assay in monocyticcells (U937) to test their anti-inflammatory properties. Cells wereplated in a 96-well cell culture plate using serum-free media. The cellswere treated with indicated concentrations of SHP-2 inhibitors for 30minutes followed by overnight stimulation with recombinant IL-6 (50ng/ml). The MCP-1 production was measured in the culture supernatantusing a MCP-1 AlphaLISA kit (Perkin Elmer).

The mixture of compounds (117+118) suppressed MCP-1 production in U937cells stimulated with IL-6 with an IC₅₀=67 nM (see FIG. 1 ). This resultindicates that compounds of the present invention should be useful fortreatment of hyperproliferative disorders associated with the immunesystem, as described herein.

Example 7: Injection Vials

A solution of 100 g of a compound of the present invention and 5 g ofdisodium hydrogenphosphate in 3 L of bidistilled water is adjusted to pH6.5 using 2 N hydrochloric acid, filtered under sterile conditions,transferred into injection vials, lyophilised under sterile conditionsand sealed under sterile conditions. Each injection vial contains 5 mgof a compound of the present invention.

Example 8: Solution

A solution is prepared from 1 g of a compound of the present invention,9.38 g of NaH₂PO₄ 2 H₂O, 28.48 g of Na₂HPO₄·12 H₂O and 0.1 g ofbenzalkonium chloride in 940 ml of bidistilled water. The pH is adjustedto 6.8, and the solution is made up to 1 L and sterilised byirradiation.

Example 9: Ampoules

A solution of 1 kg of a compound of the present invention in 60 L ofbidistilled water is filtered under sterile conditions, transferred intoampoules, lyophilised under sterile conditions and sealed under sterileconditions. Each ampoule contains 10 mg of a compound of the presentinvention.

The invention claimed is:
 1. A method of treating cancer in a subject inneed thereof, comprising administering an effective amount of a compoundaccording to formula (I):

or a pharmaceutically acceptable salt thereof, wherein X is —N— or—N(Me)- when R1 is cyclohexyl, cyclopentyl, or piperidinyl, eachoptionally substituted with 1 or two groups selected from —F, —NH₂, and—CH₂NH₂; or X is a bond when R1 is

R2 is an aryl or heteroaryl which is substituted with 1-3 groupsselected from —F, —Cl, —CF₃, C₁-C₃ alkoxy and C₁-C₃ alkyl; R3 is —H,—NH₂, —OH, —Cl, —F, —Br, or —CH₃; Y is —N—; R4 and R5 are independently—H, —NH₂, —OH, C₁-C₃ alkyl, or C₁-C₃ hydroxyalkyl; n is 0, 1, 2, or 3;and each of R9, R10, R11, R12, R13, R14, R15, and R16, when present, areindependently selected from —H, C₁-C₃ alkyl, —NH₂, —OH, —Cl, —F, —Br,C₁-C₃ aminoalkyl, C₁-C₃ hydroxyalkyl, C₁-C₃ alkoxy, and phenyl; or twoof R9, R11, R13 and R16 are taken together to form a bridged bicyclicheterocyclic system which is optionally substituted with 1-3substituents selected from C₁-C₃ alkyl, —NH₂, —OH, —Cl, —F, —Br, C₁-C₃aminoalkyl, C₁-C₃ hydroxyalkyl, C₁-C₃ alkoxy, and phenyl; or two of R9,R10, R11, R12, R13, R14, R15 and R16, which are attached to the samecarbon atom, are taken together to form a monocyclic or bicyclicspirocyclyl, which is optionally substituted with 1-3 substituentsselected from C₁-C₃ alkyl, —NH₂, —OH, —Cl, —F, —Br, C₁-C₃ aminoalkyl,C₁-C₃ hydroxyalkyl, C₁-C₃ alkoxy, and phenyl; or two of R9, R10, R11,R12, R13, R14, R15, and R16, which are attached to adjacent carbonatoms, are taken together to form a fused carbocyclyl or heterocyclyl,which is optionally substituted with 1-3 substituents selected fromC₁-C₃ alkyl, —NH₂, —OH, —Cl, —F, —Br, C₁-C₃ aminoalkyl, C₁-C₃hydroxyalkyl, C₁-C₃ alkoxy, and phenyl, to said subject.
 2. The methodof claim 1, wherein the cancer is selected from acute lymphocyticleukemia, chronic lymphocytic leukemia, acute granulocytic leukemia,adrenal cortex cancer, bladder cancer, brain cancer, breast cancer,cervical cancer, cervical hyperplasia, chorio cancer, colorectal cancer,endometrial cancer, esophageal cancer, essential thrombocytosis, gastriccancer, genitourinary carcinoma, glioma, glioblastoma,neurofibromatosis, hairy cell leukemia, head and neck carcinoma,Hodgkin's disease, Kaposi's sarcoma, kidney cancer, lung carcinoma,lymphoma, malignant carcinoid carcinoma, malignant hypercalcemia,malignant melanoma, malignant pancreatic insulinoma, medullary thyroidcarcinoma, melanoma, multiple myeloma, mycosis fungoides, myeloidleukemia, lymphocytic leukemia, neuroblastoma, non-Hodgkin's lymphoma,non-small cell lung cancer, osteogenic sarcoma, ovarian carcinoma,pancreatic carcinoma, polycythemia vera, primary brain carcinoma,primary macroglobulinemia, prostatic cancer, renal cell carcinoma,rhabdomyosarcoma, skin cancer, small-cell lung cancer, soft-tissuesarcoma, squamous cell cancer, stomach cancer, testicular cancer,thyroid cancer and Wilm's tumor.
 3. The method of claim 1, wherein thecancer is selected from non-small cell lung cancer, small cell lungcancer, breast cancer, esophageal cancer, gastric cancer, colorectalcancer, glioblastoma, pancreatic cancer, osteosarcoma, melanoma andkidney cancer.
 4. The method of claim 1, further comprisingadministering to the subject one or more additional therapeutic agents.5. The method of claim 4, wherein the one or more additional therapeuticagents is an EGFR inhibitor, MET inhibitor, PD-L1 inhibitor, MEK 1/2inhibitor, TGF-βR pathway inhibitor, or a combination thereof.
 6. Themethod of claim 5, wherein the one or more additional therapeutic agentsis Erbitux, tepotinib, avelumab, pimasertib or a combination thereof.